Thieno-[2,3-d]pyrimidine and thieno-pyridazine compounds and methods of use

ABSTRACT

The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I 
                         
wherein A 1 , A 2 , B, R 2  and R 3  are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of kinase mediated diseases including rheumatoid arthritis, psoriasis and other inflammation disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.

This application claims the benefit of U.S. Provisional Application No.60/793,950, filed Apr. 21, 2006 of which is hereby incorporated byreference.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical agentsand, more specifically, to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treat variousdisorders, including TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseasesand other maladies, such as inflammation and pain. The invention alsorelates to intermediates and processes useful in the preparation of suchcompounds.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of enzymes, which catalyze thephosphorylation of target protein substrates. The phosphorylation isusually a transfer reaction of a phosphate group from ATP to the proteinsubstrate. Common points of attachment for the phosphate group to theprotein substrate include, for example, a tyrosine, serine or threonineresidue. For example, protein tyrosine kinases (PTKs) are enzymes, whichcatalyze the phosphorylation of specific tyrosine residues in cellularproteins. Examples of kinases in the protein kinase family include,without limitation, abl, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-Met,c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9,CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck,IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros,tie, tie2, TRK, Yes, and Zap70. Due to their activity in numerouscellular processes, protein kinases have emerged as importanttherapeutic targets.

Protein kinases play a central role in the regulation and maintenance ofa wide variety of cellular processes and cellular function. For example,kinase activity acts as molecular switches regulating inflammatorycytokine production via various pathways. Uncontrolled or excessivecytokine production has been observed in many disease states, andparticularly in those related to inflammation.

The p38 protein kinase has been reported to be involved in theregulation of inflammatory cytokines. Interleukin-1 (IL-1) and TumorNecrosis Factor α (TNF-α) are pro-inflammatory cytokines secreted by avariety of cells, including monocytes and macrophages, in response tomany inflammatory stimuli (e.g., lipopolysaccharide—LPS) or externalcellular stress (e.g., osmotic shock and peroxide).

Elevated levels of TNF-α over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type II diabetes; boneresorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNF-α.

TNF-α has been reported to play a role in head trauma, stroke, andischemia. For instance, in animal models of head trauma (rat), TNF-αlevels increased in the contused hemisphere (Shohami et al., J. Cereb.Blood Flow Metab. 14:615 (1994)). In a rat model of ischemia wherein themiddle cerebral artery was occluded, the levels of TNF-α mRNA of TNF-αincreased (Feurstein et al., Neurosci. Lett. 164:125 (1993)).Administration of TNF-α into the rat cortex has been reported to resultin significant neutrophil accumulation in capillaries and adherence insmall blood vessels. TNF-α promotes the infiltration of other cytokines(IL-1β, IL-6) and also chemokines, which promote neutrophil infiltrationinto the infarct area (Feurstein, Stroke, 25:1481 (1994)).

TNF-α appears to play a role in promoting certain viral life cycles anddisease states associated therewith. For instance, TNF-α secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al., J. Immunol., 142:431 (1989)).Lahdevirta et al., (Am. J. Med., 85:289 (1988)) discussed the role ofTNF-α in the HIV associated states of cachexia and muscle degradation.

TNF-α is upstream in the cytokine cascade of inflammation. As a result,elevated levels of TNF-α may lead to elevated levels of otherinflammatory and proinflammatory cytokines, such as IL-1, IL-6, andIL-8. Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type IIdiabetes; bone resorption diseases; ischemia reperfusion injury;atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock;and toxic shock syndrome. Viruses sensitive to TNF-α inhibition, e.g.,HIV-1, HIV-2, HIV-3, are also affected by IL-1.

TNF-α and IL-1 appear to play a role in pancreatic β cell destructionand diabetes. Pancreatic β cells produce insulin which helps mediateblood glucose homeostasis. Deterioration of pancreatic β cells oftenaccompanies type I diabetes. Pancreatic β cell functional abnormalitiesmay occur in patients with type II diabetes. Type II diabetes ischaracterized by a functional resistance to insulin. Further, type IIdiabetes is also often accompanied by elevated levels of plasma glucagonand increased rates of hepatic glucose production. Glucagon is aregulatory hormone that attenuates liver gluconeogenesis inhibition byinsulin. Glucagon receptors have been found in the liver, kidney andadipose tissue. Thus glucagon antagonists are useful for attenuatingplasma glucose levels (WO 97/16442, incorporated herein by reference inits entirety). By antagonizing the glucagon receptors, it is thoughtthat insulin responsiveness in the liver will improve, therebydecreasing gluconeogenesis and lowering the rate of hepatic glucoseproduction.

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 have led to an acute and destructive form ofarthritis (Chandrasekhar et al., Clinical Immunol Immunopathol., 55:382(1990)). In studies using cultured rheumatoid synovial cells, IL-1 is amore potent inducer of stromelysin than is TNF-α (Firestein, Am. J.Pathol., 140:1309 (1992)). At sites of local injection, neutrophil,lymphocyte, and monocyte emigration has been observed. The emigration isattributed to the induction of chemokines (e.g., IL-8), and theup-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw.,5:517-531 (1994)).

IL-1 also appears to play a role in promoting certain viral life cycles.For example, cytokine-induced increase of HIV expression in achronically infected macrophage line has been associated with aconcomitant and selective increase in IL-1 production (Folks et al., J.Immunol., 136:40 (1986)). Beutler et al. (J. Immunol., 135:3969 (1985))discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J.Med., 308:553 (1983)) discussed the role of IL-1 in muscle degeneration.

In rheumatoid arthritis, both IL-1 and TNF-α induce synoviocytes andchondrocytes to produce collagenase and neutral proteases, which leadsto tissue destruction within the arthritic joints. In a model ofarthritis (collagen-induced arthritis (CIA) in rats and mice),intra-articular administration of TNF-α either prior to or after theinduction of CIA led to an accelerated onset of arthritis and a moresevere course of the disease (Brahn et al., Lymphokine Cytokine Res.,11:253 (1992); and Cooper, Clin. Exp. Immunol., 898:244 (1992)).

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated by the chemotacticnature of IL-8, including, but not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels may lead to diminished neutrophil infiltration.

Several approaches have been taken to block the effect of TNF-α. Oneapproach involves using soluble receptors for TNF-α (e.g., TNFR-55 orTNFR-75), which have demonstrated efficacy in animal models ofTNF-α-mediated disease states. A second approach to neutralizing TNF-αusing a monoclonal antibody specific to TNF-α, cA2, has demonstratedimprovement in swollen joint count in a Phase II human trial ofrheumatoid arthritis (Feldmann et al., Immunological Reviews, 195-223(1995)). These approaches block the effects of TNF-α and IL-1 by eitherprotein sequestration or receptor antagonism.

Yet another approach to block the effect of TNF-α has been to modulatethe activity of the p38 kinase enzyme. For example, the PCT publication,WO 04/010995, published on Feb. 5, 2004, describes fused heteroarylderivatives for use as P38 kinase inhibitors in the treatment of I.A.rheumatoid arthritis; PCT publication, WO 2005/009937, published on Feb.3, 2005, describes 5-membered heterocycle-based P38 kinase inhibitors;U.S. Pat. No. 6,635,644, issued Oct. 21, 2003, describes fusednitrogen-containing bicyclic ring systems as P38 inhibitors; and U.S.Pat. No. 6,794,380, issued Sep. 21, 2004, describes amide derivatives asP38 inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful in theprophylaxis and treatment of inflammatory diseases, such as TNF-α,IL-1β, IL-6 and/or IL-8 mediated diseases, as well as pain and diabetes.Accordingly, the invention also comprises pharmaceutical compositionscomprising the compounds, methods for the prophylaxis and treatment ofTNF-α, IL-1β, IL-6 and/or IL-8 mediated diseases, such as inflammatory,pain and diabetes diseases, using the compounds and compositions of theinvention, and intermediates and processes useful for the preparation ofthe compounds of the invention.

The compounds provided by the invention, including stereoisomers,tautomers, solvates, pharmaceutically acceptable salts, derivatives orprodrugs thereof, are defined by general Formula I

wherein A¹, A², B, R² and R³ are as described below. The invention alsoprovides procedures for making compounds of Formula I, and intermediatesuseful in such procedures.

The compounds provided by the invention are capable of modulating kinaseenzymes such as p38 kinase. To this end, the invention further providesfor the use of these compounds for therapeutic, prophylactic, acuteand/or chronic treatment of kinase mediated diseases, such as thosedescribed herein.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are defined by general Formula I:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

one of A¹ and A² is CR¹ and the other of A¹ and A² is N;

B is a direct bond, —(CR⁴R⁵)_(m)—, —C(═O)—, —N(R⁶)—, —O—, or—S(═O)_(m)—, wherein m is 0, 1 or 2;

R¹ is —(CR⁷R⁷)_(n)X or —(CR⁷R⁸)_(n)X, wherein n is 0, 1 or 2 and X isabsent, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸,C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),OC(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁸ or a 5-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein said ring system is optionally substituted independently withone or more substituents of R⁵, R⁸ or R⁹;

R² is H, halo, haloalkyl, NO₂, CN, OR⁷, SR⁷, NR⁷R⁸, C(O)R⁷, COOR⁷,C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸,OC(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷, NR⁷S(O)₂R⁸,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁸ or R⁹;

R³ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein said ring system is substituted independently with one or moresubstituents of R¹⁰, R¹¹, R¹⁶, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹,C(O)R¹⁰, C(S)R¹⁰, C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰,OC(O)R¹⁰, COOR¹⁰, C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹,C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰),NR¹⁰(COOR¹¹), NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹,S(O)₂R¹⁰, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹;

R⁴ is H, halo, haloalkyl, NO₂, CN, SR⁷, OR⁷, C(O)R⁷, COOR⁷, OC(O)R⁷,NR⁷R⁷, NR⁷R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁸,S(O)NR⁷R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁸ or R⁹;

R⁵ is H, CN or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R⁸ or R⁹;

R⁶ is H, CN or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R⁸ or R⁹;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸,OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR¹¹, R¹² or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹,OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹², NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹),NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹, S(O)₂R¹²,S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²R¹²,NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ or NR¹²S(O)₂R¹²;

R¹¹ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl,tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino,isopropylamino, oxo, acetyl, benzyl, cyclopropyl, cyclobutyl or apartially or fully saturated or unsaturated 5-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino,benzyl or phenyl.

In another embodiment, the compounds provided herewith, orstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are generally defined by Formula II

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

A is CR⁴ or N;

R² is H, halo, haloalkyl, NO₂, CN, OR^(7a), SR^(7a), NR^(7a)R^(7a),C(O)R^(7a), COOR^(7a), C(O)NR^(7a)R^(7a), C(O)NR^(7a)R^(7b),NR^(7a)C(O)R^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)NR^(7a)R^(7a),NR^(7a)C(O)NR^(7a)R^(7b), OC(O)NR^(7a)R^(7b), S(O)₂R^(7a),S(O)₂NR^(7a)R^(7a), S(O)₂NR^(7a)R^(7b), NR^(7a)S(O)₂R^(7a),NR^(7a)S(O)₂R^(7b), C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R^(7a) or R⁹;

R³ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein said ring system is substituted independently with one or moresubstituents of R¹⁰, R¹¹, R¹⁶, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰SR¹⁰, OR¹¹, SR¹¹,C(O)R¹⁰, C(S)R¹⁰, C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰,OC(O)R¹⁰, COOR¹⁰, C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹,C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰),NR¹⁰(COOR¹¹), NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹,S(O)₂R¹⁰, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹, provided that at least one substituent onR³ is NR¹⁰R¹⁰, NR¹⁰R¹¹, C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰, C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)SR¹⁰, C(O)SR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹,C(S)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹,NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹,NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹), OC(O)NR¹⁰R¹¹, S(O)₂R¹⁰, S(O)₂R¹¹,S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹;

R⁴ is H or is absent;

R⁵ is H, halo, haloalkyl, NO₂, CN, SR^(7a), OR^(7a), C(O)R^(7a),COOR^(7a), OC(O)R^(7a), NR^(7a)R^(7a), NR^(7a)R^(7b), C(O)NR^(7a)R^(7a),C(O)NR^(7a)R^(7b), NR^(7a)C(O)R^(7a), NR^(7a)C(O)R⁸, NR⁷C(O)NR^(7a)R⁸,S(O)NR^(7a)R^(7b), S(O)₂NR^(7a)R^(7b), NR^(7a)S(O)NR^(7a)R^(7b),NR^(7a)S(O)₂NR^(7a)R^(7b), C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R⁸ or R⁹;

R⁶ is H, CN or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R⁸ or R⁹;

alternatively, R⁵ and R⁶ taken together with the carbon or nitrogen atomto which they are attached form a saturated or partially or fullyunsaturated 5-6 membered monocyclic or 7-10 membered bicyclicheterocyclic ring optionally including 1-3 additional heteroatomsselected from O, N, or S, and optionally substituted independently with1-5 substituents of R⁸ or R⁹;

R^(7a) is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl or partially or fully saturated orunsaturated 5-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl andpartially or fully saturated 5-6 membered heterocyclic optionallysubstituted with one or more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸,OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R^(7b) is H or C₁₋₁₀-alkyl;

alternatively, R^(7a) and R^(7b) taken together with the nitrogen atomto which they are attached form a saturated or partially or fullyunsaturated 5-6 membered monocyclic or 7-10 membered bicyclicheterocyclic ring optionally including 1-3 additional heteroatomsselected from O, N, or S, and optionally substituted independently with1-5 substituents of R⁸ or R⁹;

R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, oxo, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR¹¹, R¹² or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹,OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²;

R¹¹ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴, SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a partially or fully saturated or unsaturated 5-8 membered or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl,tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino,isopropylamino, oxo, acetyl, benzyl, cyclopropyl, cyclobutyl or apartially or fully saturated or unsaturated 5-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino,benzyl or phenyl.

In another embodiment, the compounds of Formula I include N as A¹ andCR¹ as A², in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N as A² andCR¹ as A¹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include B as a directbond, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include —(CR⁵R⁶)_(m)—as B, wherein m is 0, 1 or 2, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I include —C(═O)— as B,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include —N(R⁶)— as B,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include —O— as B, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include —S(═O)_(m)— asB, wherein m is 0, 1 or 2, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include —C(R⁷R⁷)_(n)Xor —C(R⁷R⁸)_(n)X as R¹, wherein n is 0, 1 or 2 and X is NR⁷R⁷, NR⁷R⁸,OR⁷; SR⁷, OR⁸; SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸, COOR⁸,C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷,NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸,NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷,NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁸, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include a 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system as R¹, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein said ring system is optionally substitutedindependently with one or more substituents of R⁵, R⁸ or R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I or II include H, halo,haloalkyl, NO₂, CN, OR⁷, SR⁷, NR⁷R⁸, C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl as R², inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I or II include COOR⁷,C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸,OC(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸ asR², in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I or II include H orC₁₋₁₀-alkyl as R², in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I optionally include oneor more substituents of R¹⁰, R¹¹, R¹⁶, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰,OR¹¹, SR¹¹, C(O)R¹⁰, C(S)R¹⁰, C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹,C(O)C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰, C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹,C(O)SR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,OC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹,NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹,NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹), NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹,NR¹⁰C(O)C(O)NR¹⁰R¹¹, S(O)₂R¹⁰, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹ on R³, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula II include at least onesubstituent of NR¹⁰R¹⁰, NR¹⁰R¹¹, S(O)₂R¹⁰, S(O)₂R¹¹, C(O)NR¹⁰R¹⁰,C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰,NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹ on R³, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I or II include twosubstituents on R³, a first substituent of NR¹⁰R¹⁰, NR¹⁰R¹¹, S(O)₂R¹⁰,S(O)₂R¹¹, C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹ and a second substituentof R¹⁶, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I or II include phenyl,naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzoxazolyl, benzopyrazolyl, benzisoxazolyl, benzothiazolyl orbenzimidazolyl as R³, each of which has one substituent of NR¹⁰R¹⁰,NR¹⁰R¹¹, C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰, C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹⁰,C(O)SR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰),NR¹⁰(COOR¹¹), OC(O)NR¹⁰R¹¹, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹, and 1-3 optionalsubstituents of R¹⁰, R¹¹, R¹⁶, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹,C(O)R¹⁰, C(S)R¹⁰, C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰,OC(O)R¹⁰, COOR¹⁰, C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹,C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰),NR¹⁰(COOR¹¹), NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹,S(O)₂R¹⁰, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I or II include onesubstituent of NR¹⁰R¹⁰, NR¹⁰R¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹,C(S)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹,NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹,S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹ and 0-3 substituents of R¹⁶, on R³.

In another embodiment, the compounds of Formula I or II include H, halo,haloalkyl, NO₂, CN, NR⁷R⁷, NR⁷R⁸, OR⁷; SR⁷, C(O)R⁷, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl asR⁴, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include OC(O)R⁷,COOR⁷, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁸C(O)NR⁷R⁸,NR⁷(COOR⁷), OC(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷,NR⁷S(O)₂R⁷ as R⁴, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I or II include H orC₁₋₁₀-alkyl as R⁴, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include N as A¹, CR¹as A², and phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, benzisoxazolyl, benzopyrazolyl,benzothiazolyl or benzimidazolyl as R³, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I include NR⁷R⁷, NR⁷R⁸,OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), C(O)NR⁷R⁸, C(S)NR⁷R⁸,NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁸ or a ring system selected from phenyl, naphthyl, pyridyl,pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl as R¹in conjunction with any of the above or below embodiments, wherein saidring system is optionally substituted independently with 1-5substituents of R⁷, R⁸, R⁹, oxo, OR⁷, SR⁷, C(O)R⁷, NR⁷R⁷, NR⁷R⁸, OR⁸,SR⁸, C(O)R⁸, COOR⁷, OC(O)R⁷, COOR⁸, OC(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸,NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O₂)NR⁷R⁷ or NR⁷S(O)₂NR⁷R⁸.

In another embodiment, there are provided compounds of Formula I whereinA¹ is CR¹;

A² is N;

B is a direct bond;

R¹ is —(CR⁷R⁸)_(n), wherein n is 1 or 2, NR⁷R⁷, NR⁷R⁸, OR⁷; SR⁷, OR⁸,SR⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), S(O)₂NR⁷R⁷,NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁸ or aring system selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzothiazolyl, benzisoxazolyl, benzopyrazolyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, wherein the ring system is optionallysubstituted independently with 1-5 substituents of R⁷R⁸, R⁹, oxo, OR⁷,SR⁷, C(O)R⁷, NR⁷R⁷, NR⁷R⁸, OR⁸, SR⁸, C(O)R⁸, COOR⁷, OC(O)R⁷, COOR⁸,OC(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O₂)NR⁷R⁷ or NR⁷S(O)₂NR⁷R⁸;

R² is H or C₁₋₁₀-alkyl;

R³ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl orbenzimidazolyl, said R³ substituted with one substituent of NR¹⁰R¹⁰,NR¹⁰R¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰,S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹ and 0-3substituents of R¹⁶;

R⁴ is H or C₁₋₁₀-alkyl;

R⁵ is H or C₁₋₁₀-alkyl;

R⁶ is H or C₁₋₁₀-alkyl;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl andC₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzisoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, eachof which is optionally substituted independently with 1-5 substituentsof R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹, COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹,NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or apartially or fully saturated or unsaturated 5-6 membered ring of carbonatoms optionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, andC₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of R¹¹, R¹² orR¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²;

R¹¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, each of which is optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, R¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, each of which is optionally substitutedindependently with 1-3 substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl,tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino,isopropylamino, oxo, acetyl, benzyl, cyclopropyl, cyclobutyl or apartially or fully saturated or unsaturated 5-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino,benzyl or phenyl.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is NR⁷R⁷, NR⁷R⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, NR⁷C(O)R⁷,C(O)NR⁷R⁸, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁸ ora ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, wherein the ring system isoptionally substituted independently with 1-3 substituents of R⁷, R⁸,R⁹, oxo, OR⁷, SR⁷, C(O)R⁷, NR⁷R⁷, NR⁷R⁸, OR⁸, SR⁸, C(O)R⁸, COOR⁷,OC(O)R⁷, COOR⁸, OC(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O₂)NR⁷R⁷ orNR⁷S(O)₂NR⁷R⁸;

R² is H;

R³ is

wherein

-   -   one of A⁶ and A⁷ is CR^(3a) and the other of A⁶ and A⁷ is        CR^(3b) or N;    -   each of A⁵, A⁸, A⁹, A¹⁰ and A¹¹ is, independently, CR^(3b) or N;    -   X² is CR^(3a);    -   each of X¹, X³ and X⁴ is, independently, CR^(3b) or N;    -   Y¹ is CR^(3b)R^(3c), NR^(3c), O or S;    -   Y² is CR^(3a)R^(3b) or NR^(3a); and    -   Z is CH or N;    -   R^(3a) is NR¹⁰R¹⁰, NR¹⁰R¹¹, C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹,        NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,        S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or        NR¹⁰S(O)₂R¹¹;    -   R^(3b) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; and    -   R^(3c) is H, CN or C₁₋₁₀-alkyl;

R⁴ is H;

R⁵ is H;

R⁶ is H;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₃₋₆-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₃₋₆-cycloalkyl optionally substitutedwith 1-3 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹),OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹,NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is phenyl, naphthyl, pyridyl, pyrimidyl, quinolinyl, isoquinolinyl,quinazolinyl, thiophenyl, furyl, pyrrolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which isoptionally substituted independently with 1-3 substituents of R⁹, oxo,NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹, COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹,OC(O)NR⁹R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and optionallysubstituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-3substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl ring of said ringsystem is optionally substituted independently with 1-3 substituents ofhalo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, andC₃₋₁₀-cycloalkyl optionally substituted with 1-3 substituents of R¹¹,R¹², R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²; and

R¹¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, each of which is optionally substitutedindependently with 1-3 substituents of R¹², R¹³ or R¹⁶.

In another embodiment, the compounds are generally defined by Formula Ior II above, wherein R³ is

wherein

-   -   one of A⁶ and A⁷ is CR^(3a) and the other of A⁶ and A⁷ is        CR^(3b) or N;    -   each of A⁵, A⁸, A⁹, A¹⁰ and A¹¹ is, independently, CR^(3b) or N;    -   X² is CR^(3a);    -   each of X¹, X³ and X⁴ is, independently, CR^(3b) or N;    -   Y¹ is CR^(3b)R^(3c), NR^(3c), O or S;    -   Y² is CR^(3a)R^(3b) or NR^(3a); and    -   Z is CH or N;    -   R^(3a) is NR¹⁰R¹⁰, NR¹⁰R¹¹, C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹,        NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,        S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or        NR¹⁰S(O)₂R¹¹;    -   R^(3b) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; and

R^(3c) is H, CN or C₁₋₁₀-alkyl, in conjunction with any of the above orbelow embodiments of compounds of Formula I or II.

In another embodiment, the compounds are generally defined by Formula Ior II above, wherein R³ is

wherein

-   -   each of A⁵, A⁶, and A⁷ is, independently, CR^(3b) or N;    -   A⁸ is CR^(3c) or N; and    -   A⁹ is CR^(3d) or N;    -   Y¹ is O or S;    -   Y² is NR^(3a);    -   R^(3a) is NR¹⁰R¹⁰, NR¹⁰R¹¹, C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹,        NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,        S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or        NR¹⁰S(O)₂R¹¹;    -   R^(3b) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;

R^(3c) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;

-   -   R^(3c) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;    -   R^(3d) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; and

alternatively, R^(3c) and R^(3d) taken together with the atoms to whichthey are attached form a phenyl or tetrahydrofuranyl ring system,optionally substituted with 1-3 substituents of halo, haloalkyl, CN,NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,in conjunction with any of the above or below embodiments of compoundsof Formula I or II.

In another embodiment, the compounds of Formula II include R⁵ and R⁶,taken together with the nitrogen to which they are attached, forming asaturated or partially or fully unsaturated 5-6 membered monocyclic or7-10 membered bicyclic heterocyclic ring optionally including 1-3additional heteroatoms selected from O, N, or S, and optionallysubstituted independently with 1-5 substituents of R⁸ or R⁹, inconjunction with any of the above or below embodiments of compounds ofFormula II.

In another embodiment, the compounds of Formula II include R⁵ and R⁶,taken together with the nitrogen to which they are attached, forming aheterocyclic ring selected from pyrrolidinyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl and piperazinyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁸ or R⁹, in conjunction with any of the above or belowembodiments of compounds of Formula II.

In yet another embodiment, the compounds of Formula I or II include theexamples described hereinbelow.

DEFINITIONS

The following definitions should assist in understanding the inventiondescribed herein.

The terms “agonist” and “agonistic” when used herein refer to ordescribe a molecule which is capable of, directly or indirectly,substantially inducing, promoting or enhancing biological activity of abiological molecule, such as an enzyme or receptor, including Tie-2 andLck.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s), but not excluding other elements.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀). The term“alkyl” radicals include “lower alkyl” radicals having one to about sixcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,hexyl and the like. The term “alkylenyl” embraces bridging divalentalkyl radicals such as methylenyl and ethylenyl.

The term “alkenyl”, when used alone or in combination, embraces linearor branched radicals having at least one carbon-carbon double bond in amoiety having between two and ten carbon atoms. Included within alkenylradicals are “lower alkenyl” radicals having two to about six carbonatoms and, for example, those radicals having two to about four carbonatoms. Examples of alkenyl radicals include, without limitation,ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Theterms “alkenyl” and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations, asappreciated by those of ordinary skill in the art.

The term “alkynyl”, when used alone or in combination, denotes linear orbranched radicals having at least one carbon-carbon triple bond andhaving two to ten carbon atoms. Examples of alkynyl radicals include“lower alkynyl” radicals having two to about six carbon atoms and, forexample, lower alkynyl radicals having two to about four carbon atoms.Examples of such radicals include, without limitation, ethynyl, propynyl(propargyl), butynyl, and the like.

The term “alkoxy” or “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkylportions of one or more carbon atoms. The term alkoxy radicals include“lower alkoxy” radicals having one to six carbon atoms. Examples of suchradicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.Alkoxy radicals may be further substituted with one or more halo atoms,such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals.Examples of such radicals include fluoromethoxy, chloromethoxy,trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” ring system need not be aromatic, and the ring(s) fused to thearomatic ring may be partially or fully unsaturated and include one ormore heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. Unless otherwise specified, the “aryl”group may be substituted, such as with 1 to 5 substituents includinglower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and loweralkylamino, and the like. Phenyl substituted with —O—CH₂—O— or—O—CH₂—CH₂—O— forms an aryl benzodioxolyl substituent.

The term “carbocyclic”, also referred to herein as “cycloalkyl”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane andpartially saturated monocyclic groups such as cyclopentene, cyclohexeneor cyclohexadiene. The partially saturated groups are also encompassedin the term “cycloalkenyl” as defined below.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 5-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The terms “partially or fully saturated or unsaturated” and “saturatedor partially or fully unsaturated” with respect to each individual ring,refer to the ring either as fully aromatic (fully unsaturated),partially aromatic (or partially saturated) or fully saturated(containing no double or triple bonds therein). If not specified assuch, then it is contemplated that each ring (monocyclic) in a ringsystem (if bicyclic or tricyclic) may either be fully aromatic,partially aromatic or fully saturated, and optionally substituted withup to 5 substituents.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms and, for example, lower haloalkylradicals having one to three carbon atoms. Examples of haloalkylradicals include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perfluoroalkyl”, as used herein, refers to alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of unsaturated heteroaryl radicals, include unsaturated 5- to6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms,including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one or more heteroatomsselected from N, O or S. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered heteromonocyclic groups containing 1to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

The term “heterocycle” also embraces radicals where heterocyclicradicals are fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

Examples of partially saturated and saturated heterocyclyl include,without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The terms “alkylthio” and “thioalkoxyl” embrace radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” is methylthio,(CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.An example of “haloalkylthio” is trifluoromethylthio.

The term “aminoalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more amino radicals. Examples of aminoalkyl radicals include“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. Examples of alkylaminoalkyl radicals include “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Suitable alkylaminoalkyl radicals may be mono or dialkylsubstituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl,N,N-diethylaminomethyl and the like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. Examples of alkylaminoalkoxy radicals include“lower alkylaminoalkoxy” radicals having alkoxy radicals of one to sixcarbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkylsubstituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy,N,N-diethylaminoethoxy and the like.

The term “Formula I” includes any sub formulas, such as Formula II.Similarly, the term “Formula II” includes any sub formulas.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I or II is intended to refer to a form of thecompound that is safe for administration. For example, a free base, asalt form, a solvate, a hydrate, a prodrug or derivative form of acompound of Formula I or of Formula II, which has been approved formammalian use, via oral ingestion or any other route of administration,by a governing body or regulatory agency, such as the Food and DrugAdministration (FDA) of the United States, is pharmaceuticallyacceptable.

Included in the compounds of Formulas I and II are the pharmaceuticallyacceptable salt forms of the free-base compounds. The term“pharmaceutically-acceptable salts” embraces salts, commonly used toform alkali metal salts and to form addition salts of free acids or freebases, which have been approved by a regulatory agency. As appreciatedby those of ordinary skill in the art, salts may be formed from ionicassociations, charge-charge interactions, covalent bonding,complexation, coordination, etc. The nature of the salt is not critical,provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I and II may be prepared from an inorganic acid or from anorganic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfonic,sulfuric and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of whichinclude, without limitation, formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I and II include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I or II.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid (HCl), hydrobromic acid (HBr), citric acid, sulphuricacid and phosphoric acid and such organic acids as oxalic acid, stearicand, salicylic acid, pamoic acid, gluconic acid, ethanesulfonic acid,methanesulfonic acid (MSA), benzenesulfonic acid (BSA), toluenesulfonicacid, tartaric acid, fumaric acid, medronic acid, napsylic acid, maleicacid, succinic acid and citric acid. Other examples include salts withalkali metals or alkaline earth metals such as sodium, potassium,calcium or magnesium, or with organic bases.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66:1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is broadly construed herein, and intended toencompass any salt of a compound of this invention, any ester of acompound of this invention, or any other compound, which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to the ability to modulate akinase enzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative, which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formula I. A “pharmaceutically-acceptable prodrug” as usedherein, denotes a prodrug, which is pharmaceutically acceptable.Pharmaceutically acceptable modifications to the compounds of Formula Iare readily appreciated by those of ordinary skill in the art.

The compound(s) of Formula I or II may be used to treat a subject byadministering the compound(s) as a pharmaceutical composition. To thisend, the compound(s) can be combined with one or more carriers, diluentsor adjuvants to form a suitable composition, which is described in moredetail herein.

The term “carrier”, as used herein, denotes any pharmaceuticallyacceptable additive, excipient, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The term “leaving groups” (also denoted as “LG”) generally refer togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I and II.

The compounds of Formulas I and II can be synthesized according to theprocedures described in the following Schemes 1-5, wherein thesubstituents are as defined for Formulas I and II, above, except wherefurther noted.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

ACN, MeCN acetonitrile AgNO₃ silver nitrate BSA bovine serum albumin BOPbenzotriazol-1-yl-oxy hexafluorophosphate CDI carbonyldiimidazole Cs₂CO₃cesium carbonate CHCl₃ chloroform CH₂Cl₂, DCM dichloromethane, methylenechloride DCC dicyclohexylcarbodiimide DIC 1,3-diisopropylcarbodiimideDIEA,(iPr)₂NEt diisopropylethylamine DME dimethoxyethane DMFdimethylformamide DMAP 4-dimethylaminopyridine DMSO dimethylsulfoxideEDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Et₂O diethyl etherEtOAc ethyl acetate FBS fetal bovine serum G, gm gram h, hr hour H₂hydrogen H₂O water HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HBr hydrobromic acid HClhydrochloric acid HOBt 1-hydroxybenzotriazole hydrate HOAc acetic acidHPLC high pressure liquid chromatography IPA, IpOH isopropyl alcoholK₂CO₃ potassium carbonate KI potassium iodide LG leaving group MgSO₄magnesium sulfate MS mass spectrum MeOH methanol N₂ nitrogen NaCNBH₃sodium cyanoborohydride Na₂CO₃ sodium carbonate NaHCO₃ sodiumbicarbonate NaH sodium hydride NaOCH₃ sodium methoxide NaOH sodiumhydroxide Na₂SO₄ sodium sulfate NBS N-bromosuccinimide NH₄Cl ammoniumchloride NH₄OH ammonium hydroxide NMP N-methylpyrrolidinone P(t-bu)₃tri(tert-butyl)phosphine PBS phospate buffered saline Pd/C palladium oncarbon Pd(PPh₃)₄ palladium(0)triphenylphosphine tetrakis Pd(dppf)Cl₂palladium(1,1- bisdiphenylphosphinoferrocene) II chloride Pd(PhCN)₂Cl₂palladium di-cyanophenyl dichloride Pd(OAc)₂ palladium acetate Pd₂(dba)₃bis(dibenzylideneacetone) palladium PyBopbenzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate RTroom temperature TBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate TEA, Et₃N triethylamine TFA trifluoroacetic acid THFtetrahydrofuran UV ultraviolet light

A thieno-[2,3-d]pyrimidine compound 13 (wherein A² is N, A¹ is CR¹ and“L” is a linker “B” as designated in Formula I) can be preparedaccording to the method generally described in Scheme 1 (also referredto herein as Method A). As shown, a 1,4-dithiol-2,5-diol 1 can bereacted with an optionally substituted cyanoacetamide 2 in the presenceof a suitable base and solvent to generate an amino-thiophenecarboxamide 3. Compound 3 can be treated with an ethyl xanthate salt,such as potassium ethyl xanthate, in the presence of heat and a suitablesolvent to generate the corresponding dihydrothieno-[2,3-d]pyrimidinone4. The thiocarbonyl of compound 4 can then be converted to thecorresponding thio-methyl compound 5 by treatment with methyliodide. Thecarbonyl of the pyrimidine ring can then be converted to thecorresponding chloride 6 by treatment with a suitable chloride source,such as phosphorus oxychloride (POCl₃), as shown in scheme 1 above. Themethylsulfide compound 6 can be oxidized up to the corresponding sulfone7 with a suitable oxidizing reagent, such as oxone as shown above. Thechloro-pyrimidine 7 can be reduced to the correspondingdes-chloro-pyrimidine 8 using a suitable reducing agent, such as byhydrogenation with a suitable catalyst, such as a suitable palladiumcatalyst, as shown. The methylsulfonyl moiety of compound 8 can now bereacted with a suitable compound 9 containing a nucleophilic species,such as an oxygen, nitrogen, sulfur or carbon nucleophile, to afford thedesirably R¹-substituted pyrimidine compound 10. For example, thenucleophile (R¹) may be a nitrogen, oxygen or sulfur nucleophile(R¹=—NHR^(7 or 8), —OR^(7 or 8) or —SR^(7 or 8)), which can displace thesulfonyl of the pyrimidine in the presence of a suitable base byconventional methods, as appreciated by those skilled in the art. Heatmay or may not be required to effect the transformation depending uponthe particular substrates involved. Suitable nucleophiles are discussedin more detail in scheme 5, as well as in the examples set forth below.

Compound 10 can be converted to the corresponding bromide 11, bytreatment with a suitable source of bromine under suitable conditions,such as Br₂ or N-bromosuccinimide (commonly referred to as NBS) in thepresence suitable solvent to form the bromide adduct 11.

The bromide intermediate 11 can be reacted with a suitable boronic acid12, in the presence of a suitable catalyst in a Suzuki-type reaction, toform the desired compound 13. Formation of compound 13 may require heat,up to and including reflux temperatures depending on the particularsolvent and concentration, as appreciated by those skilled in the art.

The Suzuki method is a reaction using a borane reagent, such as adioxaborolane intermediate 12 (also described in scheme 3 below as aborane B-A intermediate 8), and a suitable leaving group containingreagent, such as the bromide compound II (Br is a leaving group “LG”,which may also be other halogens, such as an I). As appreciated to oneof ordinary skill in the art, Suzuki reactions also utilize a palladiumcatalyst. Suitable palladium catalysts include Pd(PPh₃)₄, Pd(OAc)₂ orPd(dppf)Cl₂. Where LG is a halide, the halide may be an iodide, abromide or even a chloride (chloro-pyridyl or chloro-picolinoyl B ringsundergo suzuki reactions in the presence of Pd(OAc)₂). Other LGs arealso suitable. For example, Suzuki couplings are known to occur with asulfonate, such as trifluoromethanesulfonate, as the leaving group.

The Suzuki reaction conditions may vary. For example, Suzuki reactionsare generally run in the presence of a suitable base such as a carbonatebase, bicarbonate or an acetate base, in a suitable solvent such astoluene, acetonitrile, DMF or an aqueous-organic solvent combination ora biphasic system of solvents. Further, the reaction may require heatdepending upon the particular pyrimidine 11 and/or boronic acid 12, asappreciated by those skilled in the art. In addition, where R³ is anaromatic moiety, such as phenyl, the reaction may be complete in a shortperiod of time with heat.

Further, the boronic acid 12 may be any suitable desired boronic acidhaving the general formula (RO)₂B—R³ (where “B” is absent or a directbond—see formula II) or (RO)₂B—“B”—R³, (where “B” is a spacer such as an—(CR⁵R⁶)₀₋₂—, —C(═O)—, —N(R⁶)—, —O— or —S(═O)₀₋₂—) as defined in FormulaI. The boronic acid may also be a cyclic boronate (as shown). In thisfashion, desired R³ groups such as aryl or heteroaryl R³ groups, can beinstalled into the pyrimidine (or phthalazine, not shown) core 11. Thedesired boronic acid compounds 12 may generally be made as illustratedin scheme 6 below.

Other known metal coupling chemistry, such Stille, Kumada, Negishicoupling methods, and the like, may be employed to couple pyrimidines 11(or phthalazines, see scheme 2) to desired cyclic R³-substitutedmoieties.

A thieno-pyridazine compound 21 (wherein A¹ is N, A² is CR¹ and “L” is alinker “B” as designated in Formula I) can be prepared according to themethod generally described in Scheme 2 above (also referred to herein asMethod B). As shown, a bromo-tert-butyl thiophene carboxamide 15 can bemade by successively reacting a thiophene carboxylic acid 1 with asulfonyl chloride followed by t-butyl amine. The bromide of compound 15can be replaced with a suitable or desired —B—R³ moiety or simply an R³(where “B” is absent or a direct bond, as in compounds of formula II)group using a desired boronic acid 16 in a Suzuki-type couplingprocedure, as described above in scheme 1, to provide the intermediate17. Formylation of compound 17 can be accomplished in the presence of asuitable base, such as a strong lithium base, followed by treatment withDMF to generate the corresponding formyl compound 18. Compound 18 can betreated with hydrazine in the presence of a suitable acid, such as HOAc,to generate the corresponding thieno-pyridazinone 19. The carbonyl ofthe pyridazinone ring can then be converted to the correspondingchloride 20 by treatment with a suitable chloride source, such asphosphorus oxychloride (POCl₃), as shown in scheme 1 above. The chlorideof the chloro-pyridazine 20 can be displaced with a suitablenucleophilic species 9, as described in scheme 1 above, to afford thedesirably R¹-substituted thieno-pyridazine compound 21.

A thieno-pyridazine compound 28 (wherein A¹ is N, A² is CR¹ and “B” is adirect bond) can be prepared according to the method generally describedin Scheme 3 above (also referred to herein as Method C). As shown, analdehyde-chloro-tert-butyl thiophene carboxamide 23 can be made bysuccessively reacting a chloro-tert-butyl thiophene carboxamide 22 witha strong lithium base, followed by treatment with DMF, as described inscheme 2 above. The chloride of compound 23 can be replaced with asuitable or desired —B—R³ moiety or simply an acid-substituted R³ group(a desirably substituted benzoic acid wherein n is 0-5 as shown inscheme 3 above, where “B” is absent or a direct bond) using a desiredboronic acid 24 in a Suzuki-type coupling procedure, as described abovein scheme 1, to provide the coupled adduct 25. Treatment of compound 25with hydrazine followed by conversion of the carbonyl of thecorresponding thieno-pyridazinone 26 to the corresponding chlorideintermediate (not shown) can be made using the methods described abovein Scheme 2. The carboxylic acid group of the phenyl ring of thetransitional chloride intermediate can be coupled to a suitablenucleophilic species, such as a desired amine, as illustrated, to affordthe desirably chloro-R³-substituted thieno-pyridazine compound 27. Othersuitable linker, groups on R³ can be made using the methods described inScheme 5 below. Compound 27 can then be reacted using a Suzuki-typereaction to afford desired R¹-substituted thieno-pyridazine compounds28.

Alternatively, an amino-substituted thieno-pyridazine compound 30 can beprepared according to the method generally described in Scheme 4 above(also referred to herein as Method D). As shown, chloro-B—R³-substitutedthieno-phthalazine compound 29 can then be reacted using a desirablysubstituted amino R¹ group in the presence of a suitable base, such asN,N-diisopropylamine and the like, with heat to afford the desiredamino-substituted thieno-pyridazine compounds 30.

R³ ring systems, generally designated in scheme 5 as the “B ring”, maybe substituted with various substitutions as specified herein. Forexample, the substitution may be a linker, such as amino, carboxyl,sulfonyl, amido, and urea linker, as defined herein in Formulas I andII, connecting various substitutions, including R¹⁰ groups and R¹¹ ringsystems (generally designated herein as the “A” ring) to the R³ ring(“B” ring in scheme 5 above). This linker may be attached by variouscoupling methods as described in Scheme 5. Each of the nine sub-schemes,numbered 1-9 above and described below, utilize the following meaningsfor (R)_(n), X, Nu⁻, E⁺ and m: (R)_(n) refers to n number of R¹⁰, R¹¹and R¹⁶ substitutions wherein n is an integer from 0-9; X refersgenerally to a “leaving group” such as a halide (bromine, chlorine,iodine or fluorine), alkylsulfonate and other known groups (also seedefinitions herein); Nu⁻ refers generally to a nucleophilic species suchas a primary or secondary amine, an oxygen, a sulfur or a anionic carbonspecies—examples of nucleophiles include, without limitation, amines,hydroxides, alkoxides and the like; E⁺ refers generally to anelectrophilic species, such as the carbon atom of a carbonyl, which issusceptible to nucleophilic attack or readily eliminates—examples ofsuitable electrophilic carbonyl species include, without limitation,acid halides, mixed anhydrides, aldehydes, carbamoyl-chlorides, sulfonylchlorides, acids activated with activating reagents such as TBTU, HBTU,HATU, HOBT, BOP, PyBOP and carbodiimides (DCC, EDC, CDI and the like),and other electrophilic species including halides, isocyanates,daizonium ions and the like; and m is either 0 or 1.

The coupling of ring B to A, as shown as products in sub-schemes 1-9,can be brought about using various conventional methods to link ring Band A together. For example, an amide or a sulfonamide linkage, as shownin sub-schemes 2 and 4, and 7 and 9 where the Nu− is an amine,respectively, can be made utilizing an amine on either the B or A groupsand an acid chloride or sulfonyl chloride on the other of either the Bor A groups. The reaction proceeds generally in the presence of asuitable solvent and/or base. Suitable solvents include, withoutlimitation, generally non-nucleophilic, anhydrous solvents such astoluene, CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like,including solvent combinations thereof. The solvent may range inpolarity, as appreciated by those skilled in the art. Suitable basesinclude, for example, tertiary amine bases such as DIEA, TEA, carbonatebases such as Na₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH,borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH₃,and the like. The base itself may also serve as a solvent. The reactionmay optionally be run neat, i.e., without any base and/or solvent. Thesecoupling reactions are generally fast and conversion occurs typically inambient conditions. However, depending upon the particular substrate,such reactions may require heat, as appreciated by those skilled in theart.

Similarly, carbamates as illustrated in sub-schemes 5 and 1 where Nu− isan amine, anhydrides as illustrated in sub-scheme 1 where Nu− is anoxygen, reverse amides as generally illustrated in sub-scheme 8 whereNu− is an amine and E+ is an acid chloride, ureas as illustrated insub-scheme 3, thioamides and thioureas where the respective carbonyloxygen is a sulfur, thiocarbamates where the respective carbonyl oxygenand/or carbamate oxygen is a sulfur, and the like. While the abovemethods are so described, they are not exhaustive, and other methods forlinking groups A and B together may be utilized as appreciated by thoseskilled in the art.

Although sub-schemes 1-9 are illustrated as having the nucleophilic andelectrophilic coupling groups, such as the amino group and acid chloridegroups illustrated in sub-scheme 2, directly attached to the substrate,either the A group or B ring, in question, the invention is not solimited. It is contemplated herein that these nucleophilic and/orelectrophilic coupling groups may be tethered from their respectivering. For example, the amine group on the B ring, and/or the acid halidegroup on the A group or ring, as illustrated in sub-scheme 2, may beremoved from direct attachment to the ring by a one or more atom spacer,such as by a methylene, ethylene spacer or the like. As appreciated bythose skilled in the art, such spacer may or may not affect the couplingreactions described above, and accordingly, such reaction conditions mayneed to be modified to effect the desired transformation.

The coupling methods described in sub-schemes 1-9 of scheme 5 are alsoapplicable for coupling desired A groups or rings to desired substitutedphthalazine benzoic acids (scheme 3) to synthesize desired compounds ofFormulas I and II. For example, a desirably substituted phthalazinebenzoic acid may be reacted with a desirably substituted primary orsecondary amine, such as an NHR¹⁰R¹⁰ or NHR¹⁰R¹¹ group in the presenceof a suitable solvent and a known coupling reagent, such as TBTU, HATU,CDI or others, to prepare the desired A-B amide bond, and the finalcompound of Formulas I or II.

Note that the B-A moiety illustrated in scheme 5 is connected through alinker “L”. “L” may be any linker generally defined by the R³substitutions in Formulas I and II, and particularly, it includes,without limitation, an amide, a urea, a thiourea, a thioamide, acarbamate, an anhydride, a sulfonamide and the like, allowing for spaceratoms either between ring B and L and/or between ring or group A and L,as described in Scheme 5 above.

To enhance the understanding and appreciation of the present invention,the following specific examples (starting reagents, intermediates andcompounds of Formulas I and II) are set forth. It should be appreciatedthat the above general methods and specific examples below are merelyfor exemplification purposes only and are not to be construed aslimiting the scope of this invention in any manner. In addition,compounds of Formulas I and II may be made by alternative methods,possibly utilizing alternative synthetic intermediates and reagents. Thefollowing analytical methods were used to purify and/or characterize thecompounds, and intermediates, described in the examples below.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈ (5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100%ACN. The gradient was followed by a 2 min. return to 5% ACN and about a2.5 min. re-equilibration (flush).

LC-MS Method:

Samples were run on an Agilent model-1100 LC-MSD system with an AgilentTechnologies XDB-C₈ (3.5μ) reverse phase column (4.6×75 mm) at 30° C.The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% HOAc) and solventB (ACN/0.1% HOAc) with a 9 min time period for a gradient from 10% to90% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation utilizing one of the following twocolumns and methods:

-   (A) Using a 50×100 mm column (Waters, Exterra, C18, 5 microns) at 50    mL/min. The mobile phase used was a mixture of solvent A (H₂O/10 mM    ammonium carbonate at pH about 10, adjusted with conc. NH₄OH) and    solvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH of about    10 adjusted with conc. NH₄OH). Each purification run utilized a 10    minute gradient from 40% to 100% solvent B followed by a 5 minute    flow of 100% solvent B. The gradient was followed by a 2 min return    to 40% solvent B.-   (B) Using a 20×50 mm column at 20 mL/min. The mobile phase used was    a mixture of solvent A (H₂O/0.1% TFA) and solvent B (ACN/0.1% TFA)    with a 10 min gradient from 5% to 100% solvent B. The gradient is    followed by a 2 min return to 5% ACN.    Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz instrument or a Bruker series 400 MHz instrument.Where so characterized, all observed protons are reported asparts-per-million (ppm) downfield from tetramethylsilane (TMS) or otherinternal reference in the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method. Compounds havingan isotopic atom, such as bromine and the like, are reported accordingto the detected isotopic pattern, as appreciated by those skilled in theart.

EXAMPLE 1 (Method A) Synthesis ofN-Cyclopropyl-4-methyl-3-(2-(2-morpholinoethyl)thieno[2,3-d]pyrimidin-6-yl)benzamide

Step (a): 2-Aminothiophene-3-carboxamide

1,4-Dithiane-2,5-diol (50 g, 328 mmol), and cyanoacetamide (55.2 g, 657mmol) were added to a mixture of MeOH (150 mL), water (9 mL) and TEA(6.5 g, 50 mmol). The resulting mixture was heated at about 35-40° C.for 30 minutes while stirring, and then heated to about 50-60° C. for anadditional 30 minutes with stirring. The reaction mixture was thencooled to RT and poured into a mixture of ice (70 g)/water (200 mL). Afine precipitate formed upon addition, which was filtered and driedovernight to give (66.7 g) of the title compound. MS (ES+): 143 (M+H)⁺.

Step (b): 2-Thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

2-Aminothiophene-3-carboxamide (13 g, 92 mmol) and potassiumethylxanthate (48 g, 275 mmol) were mixed together and added to DMF (300mL). The resulting mixture was heated to 150° C. for 6 hrs, then cooledto RT and concentrated on the rotovap under reduced pressure at 90° C.The residue was diluted with 300 mL of aqueous citric acid (5%) andcooled to 0° C. and stirred for 30 min. The tan powder was filtered anddried overnight to give (11.5 g) of the title compound MS (ES+): 185(M+H)⁺.

Step (c): 2-(Methylthio)thieno[2,3d]pyrimidin-4(3H)-one

To a solution of 2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one(28 g, 152 mmol) and 1N aqueous NaOH (600 mL) at RT was added methyliodide (11 mL, 182 mmol). The resulting mixture was stirred vigorouslyfor 2 hrs. The reaction mixture was cooled to 0° C. and acetic acidabout (100 mL) was added until the mixture was at a pH of about 4.5. Afine precipitate was filtered and dried overnight to afford the titlecompound as a fine tan powder (27 g). MS (ES+): 199 (M+H)⁺.

Step (d): 4-Chloro-2-(methylthio)thieno[2,3-d]pyrimidine

To a 3 L round bottom was added2-(methylthio)thieno[2,3d]pyrimidin-4(3H)-one (29 g, 146 mmol), POCl₃(224 g, 1463 mmol), and the resulting mixture was heated to reflux for 1hour. The reaction mixture was concentrated under reduced pressure at50° C. The residue was diluted with EtOAc (500 mL) at 0° C. Saturatedsodium bicarbonate (400 mL) was added slowly. The resulting mixture wasstirred vigorously at 0° C. for 1 hr and the layers were separated.Saturated sodium bicarbonate (400 mL) was added to the organic layer at0° C. slowly. The resulting mixture was stirred vigorously at 0° C. for20 min and the layers were separated. Brine (400 mL) was added to theorganic layer and stirred for five minutes and the layers were againseparated. The organic layer was dried over MgSO₄, filtered andconcentrated to afford the title compound (25 g) MS (ES+): 217 (M+H)⁺.

Step (e): 4-Chloro-2-(methylsulfonyl)thieno[2,3-d]pyrimidine

To 1 L round-bottom flask was added4-chloro-2-(methylthio)thieno[2,3-d]pyrimidine (35.0 g, 162 mmol), THF(300 mL). The solution was stirred at 0° C. and treated dropwise with asolution of OXONE (209 g, 339 mmol) in water (350 mL). The resultingmixture was stirred at RT overnight. The reaction mixture was dilutedwith EtOAc (500 mL) and water (300 mL). Separated the layers, theaqueous layer was extracted with EtOAc (3×300 mL). Organic layers werecombined, washed with brine (2×300 mL), dried over MgSO₄, filtered andconcentrated to give (33 g). MS (ES+): 249 (M+H)⁺.

Step (f): 2-(methylsulfonyl)thieno[2,3-d]pyrimidine

To 500 mL round-bottom flask was added4-chloro-2-(methylsulfonyl)thieno[2,3-d]pyrimidine (15 g, 60 mmol),ethyl alcohol (300 mL), nitrogen gas was bubbled for 5 minutes. To thissolution was added 10% palladium on activated charcoal (15 g). To theresulting mixture was bubbled hydrogen gas over night. The reactionmixture was filtered through Celite. The filtrate was concentrated togive the title compound (11.0 g). MS (ES+): 215 (M+H)⁺.

Step (g): 2-(2-morpholinoethyl)thieno[2,3-d]pyrimidine

A solution of 2-(methylsulfonyl)thieno[2,3-d]pyrimidine (1.0 g, 4.67mmol), 4-(2-aminoethyl)morpholine (1.8 g, 14.02 mmol), and1-methyl-2-pyrrolidinone (1.5 mL) was heated to 100° C. overnight. Thereaction mixture was cooled to RT and diluted with EtOAc (200 mL)/water(75 mL). The layers were separated, and the organic layer was washedsuccessively with water (4×75 mL) and brine (1×75 mL). The organic layerwas then dried over MgSO₄, filtered and concentrated to give (1.2 g) ofthe crude product. The crude product was adsorbed onto a plug of silicagel and chromatographed through a Redi-Sep pre-packed silica gel column(40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide thetitle compound (1.02 g) MS (ES+): 265 (M+H)⁺.

Step (h): 6-Bromo-2-(2-morpholinoethyl)thieno[2,3-d]pyrimidine

To a solution of 2-(2-morpholinoethyl)thieno[2,3-d]pyrimidine (1.0 g,3.79 mmol) in DCM (50 mL) at 0° C. was added a solution of bromine (1.2eq) in DCM (3 mL) dropwise. The resulting solution was stirred at 0° C.for 30 min. The reaction mixture was quenched with saturated solution ofNH₄Cl. The layers were separated, and the aqueous layer was extractedwith DCM (3×25 mL). Organic layers were combined, washed with brine(2×30 mL), dried over MgSO₄, filtered and concentrated to provide thetitle compound (0.910 g). MS (ES+): 345 (M+H)⁺.

Step (i):N-Cyclopropyl-4-methyl-3-(2-(2-morpholinoethyl)thieno[2,3-d]pyrimidin-6-yl)benzamide

A 5 ml glass microwave reaction vessel was charged with6-bromo-2-(2-morpholinoethyl)thieno[2,3-d]pyrimidine. (0.200 g, 0.582mmol),N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(0.135 g, 0.582 mmol), cesium fluoride (0.277 g, 1.75 mmol),tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.040 mmol),1,4-dioxane (1 mL, 57 mmol) and water (1 ml). The reaction mixture washeated in a Smith Synthesizer microwave reactor (Personal Chemistry,Inc., Upssala, Sweden) at 150° C. for 20 min. The reaction mixture wasdiluted with EtOAc and filtered through Celite®. The organic solutionswere evaporated under reduced pressure. The crude residue was suspendedin DCM and washed with saturated sodium bicarbonate (1×25 mL) followedby brine (1×25 mL), water (1×25 mL) and dried over MgSO₄. The organicsolutions were evaporated under reduced pressure and the residue wasadsorbed onto a plug of silica gel and chromatographed through aRedi-Sep pre-packed silica gel column (40 g), eluting with a gradient of5% to 95% MeOH in DCM to provide the title compound (0.095 g) MS (ES+):438 (M+H)⁺.

EXAMPLE 2 (Method B) Synthesis ofN-cyclopropyl-4-methyl-3-(7-morpholinothieno[2,3-d]pyridazin-2-yl)benzamide

Step (a): 5-Bromo-N-tert-butylthiophene-2-carboxamide

A mixture of 5-bromothiophene-2-carboxylic acid (10.0 g, 48 mmol) andthionyl chloride (3.5 ml, 48 mmol) was boiled under reflux for 3 hrs.Excess of thionyl chloride was removed by distillation under reducedpressure. The residue was taken up in DCM (30 ml) and a solution oftert-butylamine (7.0 g, 96 mmol) in DCM (30 ml) was added with stirring,the temperature of the mixture being kept below 10° C. The resultingsolution was stirred at 25° C. for 12 hrs, washed with water (3×20 ml)and dried over MgSO₄. The combined washings were basified to pH11 with5M KOH(aq) and extracted with DCM (3×100 ml) and dried over MgSO₄. Thecombined organic solutions were evaporated under reduced pressure togive the crude product (12.5 g). Recrystallization from (C₆H₁₂/CHCl₃)gave the pure amide (10.5 g) as a white solid. MS (ES+): 263 (M+H)⁺.

Step (b):N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide

A 15 ml glass microwave reaction vessel was charged with5-Bromo-N-tert-butylthiophene-2-carboxamide (1.5 g, 5.7 mmol),N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(1.7 g, 5.7 mmol), cesium fluoride (0.63 g, 17 mmol),tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.40 mmol),1,4-dioxane (4 ml, 57 mmol) and water (4 ml). The reaction mixture washeated in a Smith Synthesizer microwave reactor (Personal Chemistry,Inc., Upssala, Sweden) at 150° C. for 20 min. The reaction mixture wasdiluted with EtOAc and filtered through Celite and the Celite was washedwith DCM. The combined organic solutions were evaporated under reducedpressure. The crude residue was suspended in DCM and washed withsaturated sodium bicarbonate followed by brine, water and dried overMgSO₄. The organic solutions were evaporated under reduced pressure andthe crude product was adsorbed onto a plug of silica gel andchromatographed through a Redi-Sep pre-packed silica gel column (40 g),eluting with a gradient of 5% to 95% MeOH in DCM to provideN-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide(1.2 g). MS (ES+): 357 (M+H)⁺.

Step (c):N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide

In 150 mL round-bottom flask equipped with a stir bar, under N₂, wasaddedN-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide(1.2 g, 3.4 mmol) followed by anhydrous THF (100 mL). The solution wascooled down to −78° C. and butyllithium, (2.2 ml, 30 mmol) was addeddropwise over 5 min. The mixture was stirred at −78° C. for 0.5 hrs andwas added DMF (0.780 ml, 10 mmol). The mixture was stirred at −78° C.for 0.5 hr, quenched with saturated solution of NH₄Cl and then allowedto warm up to room temperature. The reaction then diluted with EtOAc(100 ml) and the layers were separated and the aqueous layer wasextracted with EtOAc (3×50 ml) and the combined organic solution waswashed with brine, water and dried over MgSO₄. The organic solutionswere evaporated under reduced pressure and the crude product wasadsorbed onto a plug of silica gel and chromatographed through aRedi-Sep pre-packed silica gel column (40 g), eluting with a gradient of5% to 95% MeOH in DCM to provideN-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide(1.01 g). MS (ES+): 385 (M+H)⁺

Step (d):N-Cyclopropyl-4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzamide

A 5 ml glass microwave reaction vessel was charged withN-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide(0.350 g, 0.910 mmol), glacial acetic acid (2.63 ml, 45.5 mmol),hydrazine (0.0875 g, 2.73 mmol). The reaction mixture was heated in aSmith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala,Sweden) at 150° C. for 20 min. The crude was concentrated andazeotropically dried with toluene, the residue was partioned betweenwater and DCM, and the aqueous layer was extracted with DCM (2×25 ml).Combined organic solution was washed with saturated solution ofNaHCO₃(aq), and dried over MgSO₄. The organic solutions were evaporatedunder reduced pressure and the crude product was adsorbed onto a plug ofsilica gel and chromatographed through a Redi-Sep pre-packed silica gelcolumn (40 g), eluting with a gradient of 5% to 95% MeOH in DCM toprovideN-Cyclopropyl-4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzamide(0.110 g) MS (ES+): 328 (M+H)⁺

Step (e):3-(7-Chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide

Heat a mixture ofN-Cyclopropyl-4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzamide(0.102 g, 0.312 mmol) POCl₃ (10 mL) at 90° C. for 2 hrs. The reactionmixture was evaporated under reduced pressure and to the crude productwas added ice (50 g) followed by careful addition of saturated solutionof NaHCO₃ (aq) extract with EtOAc, and dried over MgSO₄. The organicsolutions were evaporated under reduced pressure to provide3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide(0.056 g) MS (ES+): 345 (M+H)⁺.

Step (f):N-cyclopropyl-4-methyl-3-(7-morpholinothieno[2,3-d]pyridazin-2-yl)benzamide

A 2.5 ml glass microwave reaction vessel was charged with3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide:(0.020 g, 0.058 mmol), acetonitrile (1 ml), morpholine (0.015 g, 0.17mmol). The reaction mixture was heated in a Smith Synthesizer microwavereactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 50min. The solvent was evaporated under reduced pressure and the crudeproduct was adsorbed onto a plug of silica gel and chromatographedthrough a Redi-Sep pre-packed silica gel column (12 g), eluting with agradient of 5% to 95% MeOH in DCM to provideN-cyclopropyl-4-methyl-3-(7-morpholinothieno[2,3-d]pyridazin-2-yl)benzamide(0.016 g) MS (ES+): 395 (M+H)⁺.

EXAMPLE 3 (Method C) Synthesis ofN-cyclopropyl-3-(7-(3-fluoro-2-methoxyphenyl)thieno[2,3-d]pyridazin-2-yl)-4-methylbenzamide

Step (a): N-tert-butyl-5-chloro-3-formylthiophene-2-carboxamide

A 1 L three-neck flask was charged withN-tert-butyl-5-chlorothiophene-2-carboxamide (10.0 g, 45.9 mmol) andthoroughly flushed with nitrogen gas. The flask was charged with THF(400 ml) by cannulation, then cooled to −75° C. Tert-butyllithium, 1.7 msolution in pentane (68.4 ml, 116 mmol) was added by syringe pump over45 min, keeping the temperature less than −70° C. After stirring at −75°C. for 90 min, the reaction was gradually warmed to −60° C. and stirredfor 1 hr. The mixture was again cooled to −75° C. and DMF (14.2 ml, 184mmol) was added dropwise, ensuring the temperature remained below −70°C. The mixture was stirred at −75° C. for 1 hr. The reaction wasquenched with 200 ml sat. aq. NH₄Cl, then allowed to warm to RT. Waterwas added to the solution to dissolve solids and the mixture wasextracted with EtOAc (3×). The combined organics were dried over Na₂SO₄,filtered and concentrated to give the title compound as a tan solid(11.6 g.). MS (ESI, pos. ion) m/z: 246 (M+1).

Step (b):3-(5-(tert-butylcarbamoyl)-4-formylthiophen-2-yl)-4-methylbenzoic acid

A mixture of N-tert-butyl-5-chloro-3-formylthiophene-2-carboxamide (2.40g, 9.77 mmol),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(3.07 g, 11.7 mmol), Pd(PPh₃)₂Cl₂ (0.343 g, 0.488 mmol, Strem), andsodium carbonate (3.11 g, 29.3 mmol) in DME:EtOH:H₂O=7:2:3 (36 ml) washeated to 80° C. for 8 hrs. After cooling to RT, the mixture was dilutedwith sat. aq. NH₄Cl and extracted with EtOAc (3×). The combined organicswere dried over Na₂SO₄, filtered and concentrated over SiO₂. Columnchromatography (MeOH/CH₂Cl₂=0→2%) gave the desired product. Yield: 2.31g.

Step (c):4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzoic acid

A solution of3-(5-(tert-butylcarbamoyl)-4-formylthiophen-2-yl)-4-methylbenzoic acid(2.30 g, 6.7 mmol) in acetic acid (20 ml) was treated with hydrazine(0.73 ml, 20 mmol) and heated to 110° C. for 8 hrs. After cooling to RTthe volatiles were removed in vacuo. The residue was recrystallized fromMeOH. Yield: 1.01 g. MS (ESI, pos. ion) m/z: 287 (M+1).

Step (d):3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide

A mixture of4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzoic acid(1.01 g, 3.53 mmol) and phosphorus oxychloride (30.0 ml, 322 mmol) washeated to 105° C. for 4 hrs. After cooling to RT, the volatiles wereremoved in vacuo. The residue was re-dissolved in DCM (50 ml) andtreated with TEA (1.49 ml, 10.6 mmol) and dropwise with cyclopropylamine(0.746 ml, 10.6 mmol). The mixture was diluted with 1 M KHSO₄ andextracted with CH₂Cl₂ (3×). The combined organics were dried overNa₂SO₄, filtered and concentrated over SiO₂. Column chromatography(MeOH/CH₂Cl₂=0→2%) afforded the desired product. Yield: 0.92 g. MS (ESI,pos. ion) m/z: 344 (M+1).

Step (e):N-cyclopropyl-3-(7-(3-fluoro-2-methoxyphenyl)thieno[2,3-d]pyridazin-2-yl)-4-methylbenzamide

A mixture of3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide(90 mg, 0.26 mmol), 3-fluoro-2-methoxyphenylboronic acid (67 mg, 0.39mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.03 mmol), and sodium carbonate (83 mg,0.78 mmol) in a mixture of DME, ethanol and H₂O (7:2:3, 2 ml) was heatedto 150° C. for 15 min in the Emrys Optimizer® microwave. The mixture wasdiluted with MeOH and concentrated over SiO₂. Column chromatography(MeOH/CH₂Cl₂=0→2%) afforded the desired product. Yield: 59 mg. MS (ESI,pos. ion) m/z: 434 (M+1).

EXAMPLE 4 Synthesis of3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-4-methylbenzamide

A mixture of4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzoic acid(1.00 g, 3.49 mmol) and phosphorus oxychloride (15.0 ml, 161 mmol), washeated to 105° C. for 2 hrs. The mixture was concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ and treated with anhydrous ammonia gasat 0° C. for 30 min. The mixture was diluted with sat aq. NaHCO₃ andextracted with 25% i-PrOH/CHCl₃ (3×). The combined organics were driedover Na₂SO₄, filtered and concentrated over SiO₂. Column chromatography(MeOH/CH₂Cl₂=0→3%) afforded the title compound. MS (ESI, pos. ion) m/z:304 (M+1).

EXAMPLE 5 Synthesis ofN-cyclopropyl-4-methyl-3-(7-((S)-3-methylmorpholino)thieno[2,3-d]pyridazin-2-yl)benzamide

A mixture of3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide(90 mg, 262 μmol) and (S)-3-methylmorpholine (79 mg, 785 μmol) in NMP (2ml) was heated to 165° C. for 48 hrs. The mixture was cooled to RT,diluted with H₂O and filtered. The solids were washed with H₂O andair-dried. The residue was purified with reverse-phase chromatography(Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95%CH₃CN/H₂O, 0.1% TFA, 10.5 min gradient) to afford the title compound. MS(ESI, pos. ion) m/z: 409 (M+1).

EXAMPLE 6 Synthesis ofN-cyclopropyl-4-methyl-3-(7-(3-oxopiperazin-1-yl)thieno[2,3-d]pyridazin-2-yl)benzamide

The title compound was prepared by a method similar to that described inExample 2.3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide(100 mg, 291 μmol), piperazin-2-one (44 mg, 436 μmol) andN,N-diisopropylethylamine (152 μl, 873 μmol) were combined in NMP (2 ml)and heated to 180° C. for 18 hrs. The mixture was cooled to RT, dilutedwith H₂O and filtered. The solids were washed with H₂O and air-dried.Both the solid and solution were collected, dissolved in DMSO andpurified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP80 A column, 150×21 mm, 20 ml/min, 10-95% CH₃CN/H₂O, 0.1% TFA, 10.5 mingradient). The residue was purified with reverse-phase chromatography(Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95%CH₃CN/H₂O, 0.1% TFA, 10.5 min gradient) to afford the title compound. MS(ESI, pos. ion) m/z: 408 (M+1).

The following compounds in Table 1 are further examples of compounds ofFormulas I and II, and were prepared by procedures analogous to thosedescribed in the Example which correlates to the method indicated.

Ex. Mass Spec No. Compound Name Obtained Method 7N-cyclopropyl-3-(2-((3- 437 A(diethylamino)propyl)amino)thieno[2,3-d]pyrimidin-6-yl)-4-methylbenzamide 8 N-cyclopropyl-3-(2-((3-(dimethylamino)-2,2- 437A dimethylpropyl)amino)thieno[2,3-d]pyrimidin-6-yl)-4- methylbenzamide 9N-ethyl-4-methyl-3-(2-((2-(4- 425 Amorpholinyl)ethyl)amino)thieno[2,3-d]pyrimidin-6- yl)benzamide 104-methyl-3-(2-((2-(4- 398 Amorpholinyl)ethyl)amino)thieno[2,3-d]pyrimidin-6- yl)benzoic acid 113-(2-((2-amino-2-methylpropyl)amino)thieno[2,3- 395 Ad]pyrimidin-6-yl)-N-cyclopropyl-4-methylbenzamide 12N-cyclopropyl-4-methyl-3-(2-((tetrahydro-2- 408 Afuranylmethyl)amino)thieno[2,3-d]pyrimidin-6- yl)benzamide 13N-cyclopropyl-4-methyl-3-(2-(((3R)-6-oxo-3- 421 Apiperidinyl)amino)thieno[2,3-d]pyrimidin-6- yl)benzamide 141,1-dimethylethyl 3-(((6-(5- 521 A ((cyclopropylamino)carbonyl)-2-methylphenyl)thieno[2,3-d]pyrimidin-2-yl)amino)methyl)-1-piperidinecarboxylate 15N-cyclopropyl-4-methyl-3-(2-((3- 421 Apiperidinylmethyl)amino)thieno[2,3-d]pyrimidin-6- yl)benzamide 16N-cyclopropyl-4-methyl-3-(2-(((1-(2,2,2- 403 Atrifluoroethyl)-3-piperidinyl)methyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide 17 N-cyclopropyl-4-methyl-3-(2-((3-(4- 451 Amorpholinyl)propyl)amino)thieno[2,3-d]pyrimidin-6- yl)benzamide 183-(2-((3-(dimethylamino)-2,2- 397 Adimethylpropyl)amino)thieno[2,3-d]pyrimidin-6-yl)-4- methylbenzamide 193-(2-((3-(dimethylamino)-2,2- 411 Adimethylpropyl)amino)thieno[2,3-d]pyrimidin-6-yl)- N,4-dimethylbenzamide20 N-cyclopropyl-3-(7-hydroxythieno[2,3-d]pyridazin-2- 326 Byl)-4-methylbenzamide 213-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl- 345 B4-methylbenzamide 22 N-cyclopropyl-3-(7-(4-fluoro-2- 418 Cmethylphenyl)thieno[2,3-d]pyridazin-2-yl)-4- methylbenzamide 23N-cyclopropyl-4-methyl-3-(7-(2-(methyloxy)-3- 417 Cpyridinyl)thieno[2,3-d]pyridazin-2-yl)benzamide 24N-cyclopropyl-4-methyl-3-(7-(2- 400 Cmethylphenyl)thieno[2,3-d]pyridazin-2-yl)benzamide 25N-cyclopropyl-4-methyl-3-(7-(2- 416 C(methyloxy)phenyl)thieno[2,3-d]pyridazin-2- yl)benzamide 26N-cyclopropyl-3-(7-(2,4-difluorophenyl)thieno[2,3- 422 Cd]pyridazin-2-yl)-4-methylbenzamide 273-(7-(4-fluoro-2-methylphenyl)thieno[2,3-d]pyridazin- 378 C2-yl)-4-methylbenzamide

The following compounds in Tables 2 and 3 and Examples thereafter areadditional representative examples of compounds of Formula I and II, asprovided by the present invention.

TABLE 2

Ex. No. R¹ R³ R² L R¹⁰ or R¹¹ 28 4-morpholinyl 2-CH₃- H m-C(O)NH— Methylor phenyl cyclopropyl 29 1-piperazinyl 4-CH₃- H m-C(O)NH— Methyl orphenyl cyclopropyl 30 1-piperidinyl phenyl H m-C(O)NH— Methyl orcyclopropyl 31 cyclohexyl-N— 6-CH₃- H m-C(O)NH— Methyl or phenylcyclopropyl 32 morpholine-(CH₂)₂—N— 2-OCH₃- H m-C(O)NH— Methyl or phenylcyclopropyl 33 (CH₃)₂N—(CH₂)₂—N— 4-OCH₃- H m-C(O)NH— Methyl or phenylcyclopropyl 34 (C₂H₅)₂N—(CH₂)₂—N— phenyl H m-C(O)NH— Methyl orcyclopropyl 35 3-OH-1-pyrrolidinyl 6-OCH₃- H m-C(O)NH— Methyl or phenylcyclopropyl 36 3-amido-1-pyrrolidinyl 6-OCH₃- H m-C(O)NH— Methyl orphenyl cyclopropyl 37 4-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH—Methyl or cyclopropyl 38 3-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH—Methyl or cyclopropyl 39 4N—CH₃-1-piperizinyl 4-F-phenyl H m-C(O)NH—Methyl or cyclopropyl 40 2-Cl-phenyl phenyl H m-C(O)NH— Methyl orcyclopropyl 41 2-CH₃-phenyl 6-F-phenyl H m-C(O)NH— Methyl or cyclopropyl42 4-CH₃-phenyl 2-thiophene H m-C(O)NH— Methyl or cyclopropyl 434-Cl-phenyl 3-thiophene H m-C(O)NH— Methyl or cyclopropyl 44 3-Cl-phenyl2-pyridine H m-C(O)NH— Methyl or cyclopropyl 45 3-CH₃-phenyl 3-pyridineH m-C(O)NH— Methyl or cyclopropyl 46 2-thiophene 2-CH₃- H m-C(O)NH—Methyl or phenyl cyclopropyl 47 3-thiophene 4-CH₃- H m-C(O)NH— Methyl orphenyl cyclopropyl 48 2-pyridine phenyl H m-C(O)NH— Methyl orcyclopropyl 49 4-morpholinyl 2-CH₃- H m-C(O)NH— ethyl phenyl 501-piperazinyl 4-CH₃- H m-C(O)NH— ethyl phenyl 51 1-piperidinyl phenyl Hm-C(O)NH— ethyl 52 cyclohexyl-N— 6-CH₃- H m-C(O)NH— ethyl phenyl 53morpholine-(CH₂)₂—N— 2-OCH₃- H m-C(O)NH— ethyl phenyl 54(CH₃)₂N—(CH₂)₂—N— 4-OCH₃- H m-C(O)NH— ethyl phenyl 55 (C₂H₅)₂N—(CH₂)₂—N—phenyl H m-C(O)NH— ethyl 56 3-OH-1-pyrrolidinyl 6-OCH₃- H m-C(O)NH—ethyl phenyl 57 3-amido-1-pyrrolidinyl 6-OCH₃- H m-C(O)NH— ethyl phenyl58 3-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— ethyl 594-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— ethyl 604N—CH₃-1-piperizinyl 4-F-phenyl H m-C(O)NH— ethyl 61 2-Cl-phenyl phenylH m-C(O)NH— ethyl 62 2-CH₃-phenyl 6-F-phenyl H m-C(O)NH— ethyl 634-CH₃-phenyl 2-thiophene H m-C(O)NH— ethyl 64 4-Cl-phenyl 3-thiophene Hm-C(O)NH— ethyl 65 3-Cl-phenyl 2-pyridine H m-C(O)NH— ethyl 663-CH₃-phenyl 3-pyridine H m-C(O)NH— ethyl 67 2-thiophene 2-CH₃- Hm-C(O)NH— ethyl phenyl 68 3-thiophene 4-CH₃- H m-C(O)NH— ethyl phenyl 692-pyridine phenyl H m-C(O)NH— ethyl 70 4-morpholinyl 2-CH₃- H m-C(O)NH—propyl phenyl 71 1-piperazinyl 4-CH₃- H m-C(O)NH— propyl phenyl 721-piperidinyl phenyl H m-C(O)NH— propyl 73 cyclohexyl-N- 6-CH₃- Hm-C(O)NH— propyl phenyl 74 morpholine-(CH₂)₂—N— 2-OCH₃- H m-C(O)NH—propyl phenyl 75 (CH₃)₂N—(CH₂)₂—N— 4-OCH₃- H m-C(O)NH— propyl phenyl 76(C₂H₅)₂N—(CH₂)₂—N— phenyl H m-C(O)NH— propyl 77 3-OH-1-pyrrolidinyl6-OCH₃- H m-C(O)NH— propyl phenyl 78 3-amido-1-pyrrolidinyl 6-OCH₃- Hm-C(O)NH— propyl phenyl 79 3-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH—propyl 80 4-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— propyl 814N—CH₃-1-piperizinyl 4-F-phenyl H m-C(O)NH— propyl 82 2-Cl-phenyl phenylH m-C(O)NH— propyl 83 2-CH₃-phenyl 6-F-phenyl H m-C(O)NH— propyl 844-CH₃-phenyl 2-thiophene H m-C(O)NH— propyl 85 4-Cl-phenyl 3-thiophene Hm-C(O)NH— propyl 86 3-Cl-phenyl 2-pyridine H m-C(O)NH— propyl 873-CH₃-phenyl 3-pyridine H m-C(O)NH— propyl 88 2-thiophene 2-CH₃- Hm-C(O)NH— propyl phenyl 89 3-thiophene 4-CH₃- H m-C(O)NH— propyl phenyl90 2-pyridine phenyl H m-C(O)NH— propyl 91 4-F-phenyl H CH₃ m-C(O)NH—cyclopropyl

TABLE 3

Ex. No. R¹ R³ R² L R¹⁰ or R¹¹  92 4-morpholinyl 2-CH₃-phenyl H m-C(O)NH—Methyl or cyclopropyl  93 1-piperazinyl 4-CH₃-phenyl H m-C(O)NH— Methylor cyclopropyl  94 1-piperidinyl phenyl H m-C(O)NH— Methyl orcyclopropyl  95 cyclohexyl-N— 6-CH₃-phenyl H m-C(O)NH— Methyl orcyclopropyl  96 morpholine-(CH₂)₂—N— 2-OCH₃-phenyl H m-C(O)NH— Methyl orcyclopropyl  97 (CH₃)₂N—(CH₂)₂—N— 4-OCH₃-phenyl H m-C(O)NH— Methyl orcyclopropyl  98 (C₂H₅)₂N—(CH₂)₂—N— phenyl H m-C(O)NH— Methyl orcyclopropyl  99 3-OH-1-pyrrolidinyl 6-OCH₃-phenyl H m-C(O)NH— Methyl orcyclopropyl 100 3-amido-1-pyrrolidinyl 6-OCH₃-phenyl H m-C(O)NH— Methylor cyclopropyl 101 4-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— Methylor cyclopropyl 102 3-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— Methylor cyclopropyl 103 4N—CH₃-1-piperizinyl 4-F-phenyl H m-C(O)NH— Methyl orcyclopropyl 104 2-Cl-phenyl phenyl H m-C(O)NH— Methyl or cyclopropyl 1052-CH₃-phenyl 6-F-phenyl H m-C(O)NH— Methyl or cyclopropyl 1064-CH₃-phenyl 2-thiophene H m-C(O)NH— Methyl or cyclopropyl 1074-Cl-phenyl 3-thiophene H m-C(O)NH— Methyl or cyclopropyl 1083-Cl-phenyl 2-pyridine H m-C(O)NH— Methyl or cyclopropyl 1093-CH₃-phenyl 3-pyridine H m-C(O)NH— Methyl or cyclopropyl 1102-thiophene 2-CH₃-phenyl H m-C(O)NH— Methyl or cyclopropyl 1113-thiophene 4-CH₃-phenyl H m-C(O)NH— Methyl or cyclopropyl 1122-pyridine phenyl H m-C(O)NH— Methyl or cyclopropyl 113 4-morpholinyl2-CH₃-phenyl H m-C(O)NH— ethyl 114 1-piperazinyl 4-CH₃-phenyl Hm-C(O)NH— ethyl 115 1-piperidinyl phenyl H m-C(O)NH— ethyl 116cyclohexyl-N— 6-CH₃-phenyl H m-C(O)NH— ethyl 117 morpholine-(CH₂)₂—N—2-OCH₃-phenyl H m-C(O)NH— ethyl 118 (CH₃)₂N—(CH₂)₂—N— 4-OCH₃-phenyl Hm-C(O)NH— ethyl 119 (C₂H₅)₂N—(CH₂)₂—N— phenyl H m-C(O)NH— ethyl 1203-OH-1-pyrrolidinyl 6-OCH₃-phenyl H m-C(O)NH— ethyl 1213-amido-1-pyrrolidinyl 6-OCH₃-phenyl H m-C(O)NH— ethyl 1223-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— ethyl 1234-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— ethyl 1244N—CH₃-1-piperizinyl 4-F-phenyl H m-C(O)NH— ethyl 125 2-Cl-phenyl phenylH m-C(O)NH— ethyl 126 2-CH₃-phenyl 6-F-phenyl H m-C(O)NH— ethyl 1274-CH₃-phenyl 2-thiophene H m-C(O)NH— ethyl 128 4-Cl-phenyl 3-thiophene Hm-C(O)NH— ethyl 129 3-Cl-phenyl 2-pyridine H m-C(O)NH— ethyl 1303-CH₃-phenyl 3-pyridine H m-C(O)NH— ethyl 131 2-thiophene 2-CH₃-phenyl Hm-C(O)NH— ethyl 132 3-thiophene 4-CH₃-phenyl H m-C(O)NH— ethyl 1332-pyridine phenyl H m-C(O)NH— ethyl 134 4-morpholinyl 2-CH₃-phenyl Hm-C(O)NH— propyl 135 1-piperazinyl 4-CH₃-phenyl H m-C(O)NH— propyl 1361-piperidinyl phenyl H m-C(O)NH— propyl 137 cyclohexyl-N— 6-CH₃-phenyl Hm-C(O)NH— propyl 138 morpholine-(CH₂)₂—N— 2-OCH₃-phenyl H m-C(O)NH—propyl 139 (CH₃)₂N—(CH₂)₂—N— 4-OCH₃-phenyl H m-C(O)NH— propyl 140(C₂H₅)₂N—(CH₂)₂—N— phenyl H m-C(O)NH— propyl 141 3-OH-1-pyrrolidinyl6-OCH₃-phenyl H m-C(O)NH— propyl 142 3-amido-1-pyrrolidinyl6-OCH₃-phenyl H m-C(O)NH— propyl 143 3-amido-1-piperidinyl 2-F-phenyl Hm-C(O)NH— propyl 144 4-amido-1-piperidinyl 2-F-phenyl H m-C(O)NH— propyl145 4N—CH₃-1-piperizinyl 4-F-phenyl H m-C(O)NH— propyl 146 2-Cl-phenylphenyl H m-C(O)NH— propyl 147 2-CH₃-phenyl 6-F-phenyl H m-C(O)NH— propyl148 4-CH₃-phenyl 2-thiophene H m-C(O)NH— propyl 149 4-Cl-phenyl3-thiophene H m-C(O)NH— propyl 150 3-Cl-phenyl 2-pyridine H m-C(O)NH—propyl 151 3-CH₃-phenyl 3-pyridine H m-C(O)NH— propyl 152 2-thiophene2-CH₃-phenyl H m-C(O)NH— propyl 153 3-thiophene 4-CH₃-phenyl H m-C(O)NH—propyl 154 2-pyridine phenyl H m-C(O)NH— propyl 155 4-F-phenyl H CH₃m-C(O)NH— cyclopropyl

156 158

159 160

161 162

163 164and compounds of Examples 165-167

Wherein X is CH₂, NH, O or S, and R is H, 2,4-difluoro,2-methyl-4-fluoro, and 2-pyridyl substitutions on the phenyl ring.

While the examples described above provide processes for synthesizingcompounds of Formulas I and II, other methods may be utilized to preparesuch compounds. Methods involving the use of protecting groups may beused. Particularly, if one or more functional groups, for examplecarboxy, hydroxy, amino, or mercapto groups, are or need to be protectedin preparing the compounds of the invention, because they are notintended to take part in a specific reaction or chemical transformation,various known conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they readily lend themselves, i.e. withoutundesired secondary reactions, to removal, typically accomplished bysolvolysis, reduction, photolysis or other methods of removal such as byenzyme activity, under conditions analogous to physiological conditions.It should also be appreciated that the protecting groups should not bepresent in the end-products. The specialist knows, or can easilyestablish, which protecting groups are suitable with the reactionsdescribed herein.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4^(th) edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart (1974), in H.-D. Jakubke and H. Jescheit, Aminosäuren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide und Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

Salts of a compound of the invention having a salt-forming group may beprepared in a conventional manner or manner known to persons skilled inthe art. For example, acid addition salts of compounds of the inventionmay be obtained by treatment with an acid or with a suitable anionexchange reagent. A salt with two acid molecules (for example adihalogenide) may also be converted into a salt with one acid moleculeper compound (for example a monohalogenide); this may be done by heatingto a melt, or for example by heating as a solid under a high vacuum atelevated temperature, for example from 50° C. to 170° C., one moleculeof the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplarysalt forms and their preparation are described herein in the Definitionsection of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitriles including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inselect embodiments, such starting materials are used and reactionconditions so selected as to obtain the desired compound(s).

Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

All such isomeric forms of these compounds including racemates, racemicmixtures, scalemic mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures are included in the presentinvention.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The compounds of this invention may contain heterocyclic ring systemsattached to another ring system. Such heterocyclic ring systems may beattached through a carbon atom or a heteroatom in the ring system.

Alternatively, a compound of any of the formulas described herein may besynthesized according to any of the procedures described herein. In theprocedures described herein, the steps may be performed in an alternateorder and may be preceded, or followed, by additionalprotection/deprotection steps as necessary. The procedures may furtheruse appropriate reaction conditions, including inert solvents,additional reagents, such as bases (e.g., LDA, DIEA, pyridine, K₂CO₃,and the like), catalysts, and salt forms of the above. The intermediatesmay be isolated or carried on in situ, with or without purification.Purification methods are known in the art and include, for example,crystallization, chromatography (liquid and gas phase, and the like),extraction, distillation, trituration, reverse phase HPLC and the like.Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction.

As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theinhibitor compounds described herein are known in the art and include,for example, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) edition (2001); M.Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis,Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductionsby the Alumino- and Borohydrides in Organic Synthesis, 2^(nd) edition,Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

Accordingly, in one embodiment, the present invention provides a methodof making a compound of Formula I or II, the method comprising the stepof reacting a compound 7

wherein A¹, A², R¹ and R² are as defined herein and X is a halogen, witha boronic acid having a general formula (RO)₂B—R³, to make a compound ofFormula I or II.

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion. By way of example, a compound ofthe invention may be modified to incorporate a hydrophobic group or“greasy” moiety in an attempt to enhance the passage of the compoundthrough a hydrophobic membrane, such as a cell wall.

These detailed descriptions fall within the scope, and serve toexemplify, the above-described General Synthetic Procedures which formpart of the invention. These detailed descriptions are presented forillustrative purposes only and are not intended as a restriction on thescope of the invention.

Although the pharmacological properties of the compounds of theinvention (Formulas I and II) vary with structural change, in general,activity possessed by compounds of Formulas I and II may be demonstratedboth in vitro as well as in vivo. Particularly, the pharmacologicalproperties of the compounds of this invention may be confirmed by anumber of pharmacological in vitro assays. The following exemplifiedpharmacological assays have been carried out with the compoundsaccording to the invention. Compounds of the invention were found toinhibit the activity of various kinase enzymes, including, withoutlimitation, p38 receptor kinase at doses less than 25 μM.

Biological Evaluation

The following assays were used to characterize the ability of compoundsof the invention to inhibit the production of TNF-α and IL-1-β. Thesecond assay can be used to measure the inhibition of TNF-α and/orIL-1-β in mice after oral administration of the test compounds.

Lipopolysaccharide-activated Monocyte TNF Production Assay

Isolation of Monocytes

Test compounds were evaluated in vitro for the ability to inhibit theproduction of TNF by monocytes activated with bacteriallipopolysaccharide (LPS). Fresh residual source leukocytes (a byproductof plateletpheresis) were obtained from a local blood bank, andperipheral blood mononuclear cells (PBMCs) were isolated by densitygradient centrifugation on Ficol-Paque Plus (Pharmacia). PBMCs weresuspended at 2×10⁶/mL in DMEM supplemented to contain 2% FCS, 10 mM, 0.3mg/mL glutamate, 100 U/mL penicillin G and 100 mg/mL streptomycinsulfate (complete media). Cells were plated into Falcon flat bottom, 96well culture plates (200 μL/well) and cultured overnight at 37° C. and6% CO₂. Non-adherent cells were removed by washing with 200 μL/well offresh medium. Wells containing adherent cells (˜70% monocytes) werereplenished with 100 μL of fresh medium.

Preparation of Test Compound Stock Solutions

Test compounds were dissolved in DMZ. Compound stock solutions wereprepared to an initial concentration of 10-50 μM. Stocks were dilutedinitially to 20-200 μM in complete media. Nine two-fold serial dilutionsof each compound were then prepared in complete medium.

Treatment of Cells with Test Compounds and Activation of TNF Productionwith Lipopolysaccharide

One hundred microliters of each test compound dilution were added tomicrotiter wells containing adherent monocytes and 100 μL completemedium. Monocytes were cultured with test compounds for 60 min at whichtime 25 μL of complete medium containing 30 ng/mL lipopolysaccharidefrom E. coli K532 were added to each well. Cells were cultured anadditional 4 hrs. Culture supernatants were then removed and TNFpresence in the supernatants was quantified using an ELISA.

TNF ELISA

Flat bottom, 96 well Corning High Binding ELISA plates were coatedovernight (4° C.) with 150 μL/well of 3 μg/mL murine anti-human TNF-αMAb (R&D Systems #MAB210). Wells were then blocked for 1 h at roomtemperature with 200 μL/well of CaCl₂-free ELISA buffer supplemented tocontain 20 mg/mL BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mMCaCl₂, 0.15 mM thimerosal, pH 7.4). Plates were washed and replenishedwith 100 μL of test supernatants (diluted 1:3) or standards. Standardsconsisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/mLrecombinant human TNF (R&D Systems). Plates were incubated at roomtemperature for 1 hr on orbital shaker (300 rpm); washed and replenishedwith 100 μL/well of 0.5 μg/mL goat anti-human TNF-α (R&D systems#AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40min, washed and replenished with 100 μL/well of alkalinephosphatase-conjugated streptavidin (Jackson ImmunoResearch#016-050-084) at 0.02 μg/mL. Plates were incubated 30 min, washed andreplenished with 200 μL/well of 1 mg/mL of p-nitrophenyl phosphate.After 30 min, plates were read at 405 nm on a V_(max) plate reader.

Data Analysis

Standard curve data were fit to a second order polynomial and unknownTNF-α concentrations determined from their OD by solving this equationfor concentration. TNF concentrations were then plotted vs. testcompound concentration using a second order polynomial. This equationwas then used to calculate the concentration of test compounds causing a50% reduction in TNF production.

Compounds of the invention can also be shown to inhibit LPS-inducedrelease of IL-1β, IL-6 and/or IL-8 from monocytes by measuringconcentrations of IL-1β, IL-6 and/or IL-8 by methods well known to thoseskilled in the art. In a similar manner to the above described assayinvolving the LPS induced release of TNF-α from monocytes, compounds ofthis invention can also be shown to inhibit LPS induced release ofIL-1β, IL-6 and/or IL-8 from monocytes by measuring concentrations ofIL-1β, IL-6 and/or IL-8 by methods well known to those skilled in theart. Thus, the compounds of the invention may lower elevated levels ofTNF-α, IL-1, IL-6, and IL-8 levels. Reducing elevated levels of theseinflammatory cytokines to basal levels or below is favorable incontrolling, slowing progression, and alleviating many disease states.All of the compounds are useful in the methods of treating diseasestates in which TNF-α, IL-1β, IL-6, and IL-8 play a role to the fullextent of the definition of TNF-α-mediated diseases described herein.

Lipopolysaccharide-activated THP1 Cell TNF Production Assay

THP1 cells are resuspended in fresh THP1 media (RPMI 1640, 10%heat-inactivated FBS, 1×PGS, 1×NEAA, plus 30 μM βME) at a concentrationof 1E6/mL. One hundred microliters of cells per well are plated in apolystyrene 96-well tissue culture. One microgram per mL of bacterialLPS is prepared in THP1 media and is transferred to the wells. Testcompounds are dissolved in 100% DMSO and are serially diluted 3 fold ina polypropylene 96-well microtiter plate (drug plate). HI control and LOcontrol wells contain only DMSO. One microliter of test compound fromthe drug plate followed by 10 μL of LPS are transferred to the cellplate. The treated cells are induced to synthesize and secrete TNF-α at37° C. for 3 hrs. Forty microliters of conditioned media are transferredto a 96-well polypropylene plate containing 110 μL of ECL buffer (50 mMTris-HCl pH 8.0, 100 mM NaCl, 0.05% Tween 20, 0.05% NaN₃ and 1% FBS)supplemented with 0.44 nM MAB610 monoclonal Ab (R&D Systems), 0.34 nMruthenylated AF210NA polyclonal, Ab (R&D Systems) and 44 μg/mL sheepanti-mouse M280 Dynabeads (Dynal). After a 2 hr incubation at roomtemperature with shaking, the reaction is read on the ECL M8 Instrument(IGEN Inc.). A low voltage is applied to the ruthenylated TNF-α immunecomplexes, which in the presence of TPA (the active component inOriglo), results in a cyclical redox reaction generating light at 620nM. The amount of secreted TNF-α in the presence of compound comparedwith that in the presence of DMSO vehicle alone (HI control) iscalculated using the formula: % control (POC)=(cpd−average LO)/(averageHI−average LO)*100. Data (consisting of POC and inhibitor concentrationin μM) is fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)^D))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm.

Inhibition of LPS-Induced TNF-α Production in Mice

Male DBA/1LACJ mice are dosed with vehicle or test compounds in avehicle (the vehicle consisting of 0.5% tragacanth in 0.03 N HCl) 30 minprior to lipopolysaccharide (2 mg/Kg, I.V.) injection. Ninety minutesafter LPS injection, blood is collected and the serum is analyzed byELISA for TNF-α levels.

Compounds of the invention may be shown to have anti-inflammatoryproperties in animal models of inflammation, including carageenan pawedema, collagen induced arthritis and adjuvant arthritis, such as thecarageenan paw edema model (C. A. Winter et al Proc. Soc. Exp. Biol.Med., 111:544 (1962); K. F. Swingle, in R. A. Scherrer and M. W.Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Pharmacology,Academic, New York, 13-II:33 (1974)) and collagen induced arthritis (D.E. Trentham et al J. Exp. Med., 146:857 (1977); J. S. Courtenay, Nature(New Biol.), 283:666 (1980)).

Of the compounds tested, the compounds of Examples 1-3 and 5-27exhibited activities in the monocyte assay (LPS induced TNF release)with IC₅₀ values of 5 μM or less. Of the compounds tested, the compoundsof Examples 2, 5, 8, 11-13, 15, 17-20 and 24-26 exhibited activities inthe monocyte assay (LPS induced TNF release) with IC₅₀ values of 1.0 μMor less.

Indications

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of inflammation, cancer and relateddiseases. The compounds of the invention have kinase modulatory activityin general, and kinase inhibitory activity in particular. In oneembodiment of the invention, there is provided a method of treating adisorder related to a protein kinase enzyme in a subject, the methodcomprising administering to the subject an effective dosage amount of acompound of a compound of Formulas I or II. In another embodiment, thekinase enzyme is p38.

To this end, the compounds of the invention would be useful asanti-inflammatory agents in treating inflammation, or to minimizedeleterious effects of p38.

Based on the ability to modulate p38 kinase impacting pro-inflammatorycytokine production, the compounds of the invention are also useful intreatment and therapy of p38 related and/or cytokine-mediated diseases.Particularly, these compounds can be used for the treatment ofrheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma,uveititis, acute or chronic myelogenous leukemia, pancreatic β celldestruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis,inflammatory bowel disease, adult respiratory distress syndrome (ARDS),psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis,anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia,Reiter's syndrome, type I diabetes, type II diabetes, bone resorptiondiseases, graft vs. host reaction, Alzheimer's disease, stroke,myocardial infarction, ischemia reperfusion injury, atherosclerosis,brain trauma, multiple sclerosis, cerebral malaria, sepsis, septicshock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3,cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses orherpes zoster infection, or any combination thereof, in a subject.

An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further applicable tothe treatment of inflammation, e.g. inflammatory disease or condition,of connective tissues including dermatomyositis and myositis.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis,hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals,ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacterrelated diseases, fractures, cat scratch fever, rubeosis, neovascularglaucoma and retinopathies such as those associated with diabeticretinopathy or macular degeneration.

The compounds of the invention are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.

The present invention also provides methods for the treatment of proteintyrosine kinase-associated disorders, comprising the step ofadministering to a subject in need thereof at least one compound of theFormula I or of Formula II in an amount effective therefor. Othertherapeutic agents such as those described below may be employed withthe inventive compounds in the present methods. In the methods of thepresent invention, such other therapeutic agent(s) may be administeredprior to, simultaneously with or following the administration of thecompound(s) of the present invention.

Use of the compound(s) of the present invention in treating proteintyrosine kinase-associated disorders is exemplified by, but is notlimited to, treating a range of disorders such as:

The present invention also provides for a method for treating theaforementioned disorders such as atopic dermatitis by administration ofa therapeutically effective amount of a compound of the presentinvention, which is an inhibitor of protein tyrosine kinase, to apatient, whether or not in need of such treatment.

In yet another embodiment, the compounds are useful for decreasing thelevel of, or lowering plasma concentrations of, one or more of TNF-α,IL-1β, IL-6 and IL-8 in a subject, generally a mammal and typically ahuman.

In yet another embodiment, the compounds are useful for treating a paindisorder in a subject, which is typically a human by administering tothe subject an effective dosage amount of a compound according toFormulas I or II.

In yet another embodiment, the compounds are useful for decreasingprostaglandin production in a subject, which is typically a human, byadministering to the subject an effective dosage amount of a compoundaccording to Formulas I or II.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating TNF-α, IL-1, IL-6, and IL-8 mediated diseases,cancer, and/or hyperglycemia with the compounds and/or compositions ofthis invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, advantageously between about 0.01 andabout 50 mg/kg, more advantageously about 0.01 and about 30 mg/kg, evenmore advantageously between about 0.1 and about 10 mg/kg; and even moreadvantageously between about 0.25 and about 1 mg/kg body weight may beappropriate, and should be useful for all methods of use disclosedherein. The daily dose can be administered in one to four doses per day.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered normally willbe present as an active ingredient in a pharmaceutical composition.Thus, in another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of this invention incombination with a pharmaceutically acceptable carrier, which includesdiluents, excipients, adjuvants and the like (collectively referred toherein as “carrier” materials) as described herein, and, if desired,other active ingredients. A pharmaceutical composition of the inventionmay comprise an effective amount of a compound of the invention or aneffective dosage amount of a compound of the invention. An effectivedosage amount of a compound of the invention includes an amount lessthan, equal to or greater than an effective amount of the compound; forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound is administered byadministering a portion of the composition.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,advantageously from about 1 to 500 mg, and typically from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods and practices.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or “excipients”appropriate to the indicated route of administration. If orallyadministered on a per dose basis, the compounds may be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, to form the final formulation. For example,the active compound(s) and excipient(s) may be tableted or encapsulatedby known and accepted methods for convenient administration. Examples ofsuitable formulations include, without limitation, pills, tablets, softand hard-shell gel capsules, troches, orally-dissolvable forms anddelayed or controlled-release formulations thereof. Particularly,capsule or tablet formulations may contain one or morecontrolled-release agents, such as hydroxypropylmethyl cellulose, as adispersion with the active compound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day. Formulations suitable for topicaladministration include liquid or semi-liquid preparations suitable forpenetration through the skin (e.g., liniments, lotions, ointments,creams, pastes, suspensions and the like) and drops suitable foradministration to the eye, ear, or nose. A suitable topical dose ofactive ingredient of a compound of the invention is 0.1 mg to 150 mgadministered one to four, preferably one or two times daily. For topicaladministration, the active ingredient may comprise from 0.001% to 10%w/w, e.g., from 1% to 2% by weight of the formulation, although it maycomprise as much as 10% w/w, but preferably not more than 5% w/w, andmore preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound, which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Accordingly, in yet another embodiment of the present invention, thereis provided a method of manufacturing a medicament, the methodcomprising combining an amount of a compound according to Formulas I orII with a pharmaceutically acceptable carrier to manufacture themedicament.

In yet another embodiment, there is provided a method of manufacturing amedicament for the treatment of inflammation, the method comprisingcombining an amount of a compound according to Formulas I or II with apharmaceutically acceptable carrier to manufacture the medicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of TNF-α, IL-1, IL-6, and IL-8mediated diseases, cancer, and/or hyperglycemia.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I and II may also be administered sequentially with knownanti-inflammatory agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanti-inflammatory agent.

The compounds of the invention may also be used in co-therapies withother therapeutic agents, including p38 inhibitors and CDK inhibitors,TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, andetoricoxib, NSAID's, SOD mimics or α_(v)β₃ inhibitors.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I

or a stereoisomer or pharmaceutically acceptable salt thereof, whereinA¹ is CR¹ and A² is N; B is a direct bond; R¹ is —CH(R⁷R⁷), —CH(R⁷R⁸),—C(R⁷R⁷)—CH(R⁷R⁷), —C(R⁷R⁸)—CH(R⁷R⁸), NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸,C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), S(O)₂NR⁷R⁷,NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁸ or R¹is a ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, wherein said ring system is optionallysubstituted independently with 1-3 substituents of R⁷, R⁸, R⁹, oxo, OR⁷,SR⁷, C(O)R⁷, NR⁷R⁷, NR⁷R⁸, OR⁸, SR⁸, C(O)R⁸, COOR⁷, OC(O)R⁷, COOR⁸,OC(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O₂)NR⁷R⁷ or NR⁷S(O)₂NR⁷R⁸, R²is H or C₁₋₁₀-alkyl; R³ is phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thienyl, furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, benzoxazolyl, benzopyrazolyl,benzisoxazolyl, benzothiazolyl or benzimidazolyl, said R³ substitutedwith one substituent of NR¹⁰R¹⁰, NR¹⁰R¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰,C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹,NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰,NR¹⁰C(S)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹ and 0-3 substituents of R¹⁶; each R⁷,independently, is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyland C₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-3 substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹; R⁸ is phenyl, naphthyl, pyridyl,pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thienyl, furyl, pyrrolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionallysubstituted independently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹,SR⁹, C(O)R⁹, COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹,S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated orunsaturated 5-6 membered ring of carbon atoms optionally including 1-3heteroatoms selected from O, N, or S, and optionally substitutedindependently with 1-3 substituents of R⁹; alternatively, R⁷ and R⁸taken together form a saturated or partially or fully unsaturated 5-6membered monocyclic or 7-10 membered bicyclic ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-3 substituents of R⁹;each R⁹, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; each R¹⁰, independently, is H, halo,haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₃₋₁₀-cycloalkyl, eachof the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, and C₃₋₁₀-cycloalkyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-3 substituents of R¹¹, R¹² or R¹⁶, NR¹¹R¹², NR¹²R¹²,OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹²,COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹, C(O)NR¹²R¹², NR¹²C(O)R¹²,NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹), NR¹²(COOR¹²),OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹, S(O)₂R¹², S(O)₂NR¹¹R¹²,S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹,NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ or NR¹²S(O)₂R¹²; R¹¹ is phenyl, naphthyl,pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thienyl, furyl, pyrrolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹², R¹³, R¹⁴ or R¹⁶;alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹², R¹³,R¹⁴ or R¹⁶; each R¹², independently, is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which isoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴,R¹⁵ or R¹⁶; each R¹³, independently, is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴,OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴, COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵,C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴),NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵,NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵; R¹⁴ is phenyl, naphthyl, pyridyl,pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thienyl, furyl, pyrrolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹⁵ or R¹⁶; each R¹⁵,independently, is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of whichis optionally substituted independently with 1-3 substituents of R¹⁶;and each R¹⁶, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂,OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, acetyl, benzyl, cyclopropyl, cyclobutyl ora partially or fully saturated or unsaturated 5-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino,benzyl or phenyl.
 2. The compound of claim 1 wherein R¹ is NR⁷R⁷, NR⁷R⁸,C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, NR⁷C(O)R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷,NR⁷S(O)₂R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁸ or R¹ is a ring selected from phenyl,naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thienyl, furyl, pyrrolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein the ring is optionally substituted independently with 1-3substituents of R⁷, R⁸, R⁹, oxo, OR⁷, SR⁷, C(O)R⁷, NR⁷R⁷, NR⁷R⁸, OR⁸,SR⁸, C(O)R⁸, COOR⁷, OC(O)R⁷, COOR⁸, OC(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸,NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O₂)NR⁷R⁷ or NR⁷S(O)₂NR⁷R⁸; R² is H; R³ is

wherein each of A⁵, A⁶, A⁷, A⁸, A⁹, A¹⁰ and A¹¹ is, independently,CR^(3b) or N; X² is CR^(3a); X¹ is CR^(3b) or N; Y¹ is NR^(3c), O or S;Y² is NR^(3a); R^(3a) is NR¹⁰R¹⁰, NR¹⁰R¹¹, C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹; R^(3b) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; R^(3c) is H, CN orC₁₋₁₀-alkyl; and R^(3d) is H, halo, haloalkyl, CN, NO₂, NH₂,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; each R⁷,independently, is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₃₋₆-cycloalkyl, eachof the C₃₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₃₋₆-cycloalkyl optionallysubstituted with 1-3 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹; R⁸ is phenyl, naphthyl, pyridyl, pyrimidyl, quinolinyl,isoquinolinyl, quinazolinyl, thienyl, furyl, pyrrolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each ofwhich is optionally substituted independently with 1-3 substituents ofR⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹, COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹,NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or apartially or fully saturated or unsaturated 5-6 membered ring of carbonatoms optionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-3 substituents of R⁹;alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-3substituents of R⁹; each R⁹, independently, is H, halo, haloalkyl, CN,OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated orpartially or fully unsaturated 5-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; eachR¹⁰, independently, is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl or C₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, and C₃₋₁₀-cycloalkyl optionally substituted with 1-3substituents of R¹¹, R¹², R¹⁶, NR¹¹R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹),NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹, S(O)₂R¹²,S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²R¹²,NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ or NR¹²S(O)₂R¹²; and R¹¹ isphenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thienyl, furyl, pyrrolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each ofwhich is optionally substituted independently with 1-3 substituents ofR¹², R¹³ or R¹⁶.
 3. The compound of claim 1 selected from:N-cyclopropyl-3-(2-((3-(diethylamino)propyl)amino)thieno[2,3-d]pyrimidin-6-yl)-4-methylbenzamide;N-cyclopropyl-3-(2((3-(dimethylamino)-2,2-dimethylpropyl)amino)thieno[2,3-d]pyrimidin-6-yl)-4-methylbenzamide;N-ethyl-4-methyl-3-(2((2-(4-morpholinyl)ethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide;4-methyl-3-(2-((2-(4-morpholinyl)ethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzoicacid;3-(2((2-amino-2-methylpropyl)amino)thieno[2,3-d]pyrimidin-6-yl)-N-cyclopropyl-4-methylbenzamide;N-cyclopropyl-4-methyl-3-(2-((tetrahydro-2-furanylmethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide;N-cyclopropyl-4-methyl-3-(2(((3R)-6-oxo-3-piperidinyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide;1,1-dimethylethyl3(((6-(5-((cyclopropylamino)carbonyl)-2-methylphenyl)thieno[2,3-d]pyrimidin-2-yl)amino)methyl)-1-piperidinecarboxylate;N-cyclopropyl-4-methyl-3-(2((3-piperidinylmethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide;N-cyclopropyl-4-methyl-3-(2-(((1-(2,2,2-trifluoroethyl)-3-piperidiny)methyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide;N-cyclopropyl-4-methyl-3-(2-((3-(4-morpholinyl)propyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide;3-(2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)thieno[2,3-d]pyrimidin-6-yl)-4-methylbenzamide;and3-(2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)thieno[2,3-d]pyrimidin-6-yl)-N,4-dimethylbenzamide;or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a compound according to claim 3 and apharmaceutically acceptable carrier.
 5. A method of making a compound ofFormula I according to claim 1, the method comprising the step ofreacting a compound 7

wherein R¹ as defined in claim 1 and X is a bromide or chloride, with aboronic acid having a general formula

wherein R³ is defined in claim 1, to make the compound of Formula I ofclaim
 1. 6. The compound of claim 1 having the formula

or a pharmaceutically acceptable salt thereof, wherein each of A⁵, A⁷,A⁸ and A⁹, independently, is C or N, provided no more than one of A⁵,A⁷, A⁸ and A⁹ is N; R¹ is —CH(R⁷R⁷), —CH(R⁷R⁸), —C(R⁷R⁷)—CH(R⁷R⁷),—C(R⁷R⁸)—CH(R⁷R⁸), NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, C(O)R⁸,C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷,NR⁷(COOR⁷), C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁸ or R¹ is a ring system selectedfrom phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thienyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzopyrazolyl,benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl, wherein said ring system is optionally substitutedindependently with 1-3 substituents of R⁷, R⁸, R⁹, oxo, OR⁷, SR⁷,C(O)R⁷, NR⁷R⁷, NR⁷R⁸, OR⁸, SR⁸, C(O)R⁸, COOR⁷, OC(O)R⁷, COOR⁸, OC(O)R⁸,C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)NR⁷R⁷ or NR⁷S(O)₂NR⁷R⁸; each R¹⁰,independently, is H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of theC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl optionally substituted independently with 1-3substituents of R¹⁶; R¹¹ is phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thienyl, furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, each of which is optionally substitutedindependently with 1-3 substituents of R¹⁶; each R¹⁶ independently, isH, F, Br, Cl, I, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl,tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino,isopropylamino, acetyl, benzyl, cyclopropyl, cyclobutyl or a partiallyor fully saturated or unsaturated 5-8 membered monocyclic or 6-12membered bicyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, and optionallysubstituted independently with 1-5 substituents of halo, haloalkyl, CN,NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino,dimethylamino, ethylamino, diethylamino, isopropylamino, benzyl orphenyl; and o is 0, 1 or 2.